SARMs and method of use thereof

ABSTRACT

This invention is directed to a feed composition and method of affecting the carcass composition by increasing the lean mass, reducing the fat mass, and/or reducing the percent fat mass comprising SARM compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation application of U.S. patentapplication Ser. No. 13/627,900 filed Sep. 26, 2012, now U.S. Pat. No.8,669,286, which is a Continuation application of U.S. patentapplication Ser. No. 12/730,094 filed Mar. 23, 2010, now U.S. Pat. No.8,309,603 which is a Continuation In Part application of U.S. patentapplication Ser. No. 11/785,250, filed Apr. 16, 2007, now U.S. Pat. No.7,772,433 which is a Continuation-In-Part application of U.S. patentapplication Ser. No. 10/861,905, filed Jun. 7, 2004 now U.S. Pat. No.7,803,970; and this application is a Continuation-In-Part application ofU.S. patent application Ser. No. 11/510,844, filed on Aug. 28, 2006,which claims the benefit of U.S. Provisional Patent Application No.60/712,390, filed Aug. 31, 2005; and this application is a Continuationin Part application of U.S. patent application Ser. No. 13/868,768 filedApr. 23, 2013 which is a Continuation Application from U.S. patentapplication Ser. No. 13/302,988 filed Nov. 22, 2011, now U.S. Pat. No.8,426,465, which is a Divisional Application from U.S. patentapplication Ser. No. 11/892,595, filed Aug. 24, 2007 now U.S. Pat. No.8,080,682, which claims the benefit of U.S. Provisional Application Ser.No. 60/839,665, filed Aug. 24, 2006, and U.S. Provisional ApplicationSer. No. 60/907,749, filed Apr. 16, 2007; and this application is aContinuation in Part application of U.S. patent application Ser. No.11/826,195, filed Jul. 12, 2007 which claims the benefit of U.S.Provisional Application Ser. No. 60/907,748, filed 16 Apr. 2007,60/839,665, filed Aug. 24, 2006, and 60/830,158, filed Jul. 12, 2006;and this application is a Continuation In Part application of U.S.patent application Ser. No. 11/634,380, filed Dec. 6, 2006, which is aContinuation in Part application of U.S. patent application Ser. No.11/505,363, filed Aug. 17, 2006 now abandoned, and Ser. No. 11/505,499,filed Aug. 17, 2006, now U.S. Pat. No. 7,645,898, which is aContinuation In Part application of U.S. patent application Ser. No.11/353,225, filed Feb. 14, 2006, now abandoned, which is a ContinuationIn Part application of U.S. patent application Ser. No. 11/125,159,filed May 10, 2005, now U.S. Pat. No. 7,205,437, which is a ContinuationIn Part application of U.S. patent application Ser. No. 11/062,752,filed Feb. 23, 2005 now U.S. Pat. No. 7,759,520, which is a ContinuationIn Part application of U.S. patent application Ser. No. 10/863,524,filed Jun. 9, 2004, now abandoned, all of which are hereby incorporatedby reference in their entirety.

GOVERNMENT INTEREST STATEMENT

This invention was made in whole or in part with government supportunder grant number R01 DK598006, awarded by the National Institute ofHealth; under grant number R29 CA068096 awarded by the National CancerInstitute, National Institute of Health; under grant number R15 HD35329,awarded by the National Institute of Child Health and Human Development,National Institute of Health and under grant number R01 DK59800, awardedby the National Institute of Health. The government may have certainrights in the invention.

FIELD OF THE INVENTION

This invention is directed to a feed composition and methods ofaffecting the carcass composition of an animal by the administration ofSARM compounds. According to this invention, SARMs improve meatproduction in feedlot animals by increasing the is lean mass, reducingthe fat mass and/or percent fat mass, improving feed efficiency andmodulation of meat quality.

BACKGROUND OF THE INVENTION

The production of swine for food use is an important industry in theUnited States with more than 100 million pigs produced each year. Thereis demand among producers for agents that increase productivity andperformance such as by increasing the proportion of meat per carcass,decreasing the amount of fat, decreasing the percent fat mass,increasing the feed efficiency, increasing average daily gain (ADG),decreasing feed-to-gain ratio (F:G), and modulation of meat quality.

The androgen receptor (“AR”) is a ligand-activated transcriptionalregulatory protein that mediates induction of male sexual developmentand function through its activity with endogenous androgens. Theandrogenic hormones are steroids which are produced in the body by thetestes and the cortex of the adrenal gland or can be synthesized in thelaboratory. Androgenic steroids play an important role in manyphysiologic processes, including the development of muscle and bonemass. The endogenous steroidal androgens include testosterone anddihydrotestosterone (“DHT”). Other steroidal androgens include esters oftestosterone, such as the cypionate, propionate, phenylpropionate,cyclopentylpropionate, isocarporate, enanthate, and decanoate esters,and other synthetic androgens such as 7-Methyl-Nortestosterone (“MENT’)and its acetate ester (Sundaram et al., “7 Alpha-Methyl-Nortestosterone(MENT).

Selective Androgen Receptor Modulators (SARMs) include nonsteroidalcompounds which retain the anabolic activity of endogenous androgenswith reduced androgenic activity (i.e., lesser effects in the prostate).SARMs beneficially promote muscle growth in humans and can treat,suppress, prevent, or inhibit muscle wasting.

The ability of a SARM to beneficially promote muscle growth in humanscan be used as an alternative means to promote lean muscle deposition inanimals, feedlot animals, beef cattle or finishing livestock.

Currently, Paylean® (Ractopamine hydrochloride) is the only commerciallyavailable feed additive to increase growth rates and lean efficiency infinishing swine. Ractopamine mediates its effect by stimulatingβ-adrenergic receptor.

β-adrenergic agonists are a class of chemical compounds that stimulatesβ-receptors in the autonomic nervous system. This stimulation ofβ-receptors has the effect is of promoting growth in animals when theβ-agonists are fed to the animals.

Although β-agonists are effective in promoting the production of leanmass, there are three major drawbacks which limit the market forPaylean®. The most significant drawback to using β-agonists is theincreased susceptibility to stress in treated animals resulting inincreased injuries. Secondly, the European Union has banned β-agonistsfrom use in food-producing animals since 1996. Finally, treatment withβ-agonists results in rapid desensitization of the β-adrenergicreceptors, thereby limiting the amount of time an animal can benefitfrom this treatment (typically <4 wks).

Accordingly, there is a need for methods in which new compounds may beused to improve carcass characteristics and increase lean mass gain inanimals.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides, a feed compositionfor an animal comprising a compound of formula IIIA:

whereinZ is NO₂, CN, Cl, F, Br, I, H, COR, COOH, or CONHR;Y is CF₃, alkoxy, alkyl, hydroxyalkyl, alkylaldehyde, formyl, H, F, Br,Cl, I, CN, or Sn(R)₃;R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, halogen, alkenyl or OH;R₂ is H, F, Cl, Br, I, CH₃, CF₃, OH, CN, NO₂, NHCOCH₃, NHCOCF₃, NHCOR,alkyl, arylalkyl, OR, NH₂, NHR, N(R)₂, SR;R₃ is H, F, Cl, Br, I, CN, NO₂, COR, COOH, CONHR, CF₃, Sn(R)₃;Q is H, alkyl, halogen, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃,NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR,NHSO₂CH₃, NHSO₂R, OH, OR, COR, OCOR, OSO₂R, SO₂R, SR;n is an integer of 1-4; andm is an integer of 1-3;or its isomer, pharmaceutically acceptable salt, crystal, N-oxide,hydrate or any is combination thereof.

In one embodiment, the present invention provides a method of affectingthe carcass composition of an animal comprising administering a compoundof formula IIIA.

In one embodiment, the present invention provides a method of increasinglean mass of an animal comprising administering a compound of formulaIIIA or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, crystal, N-oxide, hydrate or any combination thereof.

In one embodiment, the present invention provides a method of reducingfat mass of an animal comprising administering a compound of formulaIIIA or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, crystal, N-oxide, hydrate or any combination thereof.

In another embodiment, the methods of this invention are directed toaffecting the carcass composition of an animal; increasing lean mass ofan animal and/or reducing fat mass/percent fat mass of an animal whereinsaid animal is a feedlot animal, a beef cattle or a finishing livestock.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be understood and appreciated more fully fromthe following detailed description taken in conjunction with theappended drawings in which:

FIG. 1: Synthetic schemes for the preparation of compound of formula II.FIG. 1A is a synthetic scheme for the preparation of an (S) enantiomerof a compound of formula II (S-II). FIG. 1B is a synthetic scheme forthe preparation of an (R) enantiomer of a compound of formula II (R-II).FIG. 1C is a synthetic scheme for the preparation of an (S) enantiomerof a compound of formula II (S-II) including an oxirane intermediate.FIG. 1D is a synthetic scheme for the preparation of an (R) enantiomerof a compound of formula II (R-II) including an oxirane intermediate.FIG. 1E is a synthetic scheme for the preparation of an (S) enantiomerof a compound of formula II (S-II) involving B-ring addition prior toA-ring addition. FIG. 1F is a synthetic scheme for the preparation of an(R) enantiomer of a compound of formula II (R-II) involving B-ringaddition prior to A-ring addition. FIG. 1G is a synthetic scheme for thepreparation of an (S) enantiomer of a compound of formula II (S-II)using 2-tribromomethyl-[1,3]dioxolan-4-one intermediate and involvingB-ring addition prior to A-ring addition. FIG. 1H is a synthetic schemefor the preparation of an (R) enantiomer of a compound of formula II(R-II) using 2-tribromomethyl-[1,3]dioxolan-4-one intermediate andinvolving B-ring addition prior to A-ring addition. FIG. 1I is asynthetic scheme for preparation of a racemic mixture of a compound offormula II, involving oxazolidinedione intermediate and B ring additionprior to A ring. FIG. 1J is a synthetic scheme for preparation of aracemic mixture of a compound of formula II, involving an oxiraneintermediate and A ring addition prior to B ring. FIG. 1K is a syntheticscheme for preparation of a large scale of an (S) enantiomer of acompound of formula II (S-II). FIG. 1L is a synthetic scheme forpreparation of a large scale of an (S) enantiomer of a compound offormula II (S-II), including an oxirane intermediate.

FIG. 2: Anabolic and androgenic pharmacology of compound of formula S-IIin castrated rats (ORX).

FIG. 3: Levator ani weight effects in castrated rats for a panel ofcompounds.

FIG. 4: Prostate weight effects in castrated rats for a panel ofcompounds.

FIG. 5: Effect of compound of formula S-II on the growth performance andcarcass composition of finishing pigs. FIG. 5A shows the increase ofaverage daily gain (ADG) over the course of the study. FIG. 5B shows thedecrease feed to gain ratio. FIG. 5C shows the increased fat free leangain per day. FIG. 5D shows an increase in ADG for days 21-28.

FIG. 6: Depicts a synthetic scheme for the preparation of an (S)enantiomer of a compound of formula XXIII.

FIG. 7: Pharmacology of a compound of formula S-XXIII in intact rats.Asterisks represent statistically significant differences between theweight of the organ in the indicated group and that observed in intactanimals treated with vehicle (P<0.05).

FIG. 8: Organ weights from castrated, compound of formulaS-XXIII-treated rats presented as a percentage of intact control.*P-value<0.05 versus intact controls.

FIG. 9: Organ weight maintenance dose-response curves for a compound offormula S-XXIII and seminal vesicles (closed squares) were obtained bynonlinear regression analysis using the sigmoid Emax model inWinNonlin®.

FIG. 10: Depicts a synthetic scheme for the preparation of an (S)enantiomer of a compound of formula XXIV.

FIG. 11: Anabolic and androgenic activity of a compound of formulaS-XXIV in ORX rats.

FIG. 12: Depicts a synthetic scheme for the preparation of an (S)enantiomer of a compound of formula XXV.

FIG. 13: Anabolic and androgenic activity of a compound of formula S-XXVin ORX rats.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In the following detailed description, numerous specific details are setforth in order to provide a thorough understanding of the invention.However, it will be understood by those skilled in the art that thepresent invention may be practiced without these specific details. Inother instances, well-known methods, procedures, and components have notbeen described in detail so as not to obscure the present invention.

This invention provides, in one embodiment, feed composition for animalscomprising acylanilides characterized by the structure of formulasI-XXV. In one embodiment, the compound is a SARM. In one embodiment, thecompound and/or feed composition is useful in affecting the carcasscomposition, increasing the lean mass, reducing the fat mass of ananimal or reducing percent fat mass, increasing feed efficiency,increasing average daily gain (ADG), decreasing feed to gain ratio (F:G)of an animal, including a feedlot animal, a beef cattle or a finishinglivestock. In another embodiment, the compound and/or feed compositionis useful in increasing muscle growth of an animal, modulation of meatquality, or enhancing productive life of animals including feedlotanimals, beef cattle and finishing livestock.

In one embodiment, the compounds of this invention provide compounds,compositions and methods of treating a variety of conditions ordiseases, including, inter alia, oral testosterone replacement therapy,male contraception, maintaining sexual desire in women, osteoporosis,treating prostate cancer and/or imaging prostate cancer. In someembodiments, the compounds of this invention are nonsteroidal ligandsfor the AR and exhibit androgenic and/or anabolic activity. In someembodiments, the compounds are partial agonists or partial antagonistsin a tissue selective manner. In some embodiments, the compounds arefull agonists or full antagonists in a tissue selective manner, which insome embodiments, allows for tissue-selective androgenic and/or anaboliceffects. These agents may be active alone or in combination withprogestins or estrogens, or other agents, as herein described. In otherembodiments, the agents are agonists, antagonists, partial agonists orpartial antagonists.

In some embodiments, this invention provides compounds, which are usefulin androgen replacement therapy (ART), useful in a) improving bodycomposition; b) is increasing bone mineral density (BMD); c) increasingbone mass; d) increasing bone strength; e) improving bone function; f)decreasing fracture risk; g) increasing muscle strength; h) increasingmuscle function; i) improving exercise tolerance; j) enhancing libido;k) improving sexual performance; and/or l) improving mood and/or m)improving cognition.

In some embodiments, this invention provides synthetic processes ofpreparation of the SARM compounds of this invention. In someembodiments, the invention provides compositions comprising theselective androgen receptor modulator compounds or use of the same forbinding an AR, modulating spermatogenesis, bone formation and/orresorption, treating muscle wasting or diseases associated with musclewasting, treating prostate cancer, and/or providing hormonal therapy forandrogen-dependent conditions.

In one embodiment, the present invention provides, a compound of formula(I):

wherein Q₂ is alkyl, F, Cl, Br, I, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂,NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR; andR is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;or its isomer, pharmaceutically acceptable salt, pharmaceutical product,N-oxide, hydrateor any combination thereof.

In one embodiment, the present invention provides, a compound of formulaS-II:

-   -   or its isomer, pharmaceutically acceptable salt, pharmaceutical        product, N-oxide, hydrate or any combination thereof.

In one embodiment, the present invention provides, a compoundrepresented by the structure of formula III:

-   -   wherein        -   X is a bond, O, CH₂, NH, Se, PR, NO or NR;        -   G is O or S;        -   T is OH, OR, —NHCOCH₃, or NHCOR;        -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F,            CHF₂, CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl or OH;        -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;        -   R₂ is H, F, Cl, Br, I, CH₃, CF₃, OH, CN, NO₂, NHCOCH₃,            NHCOCF₃, NHCOR, alkyl, arylalkyl, OR, NH₂, NHR, N(R)₂, SR;        -   R₃ is H, F, Cl, Br, I, CN, NO₂, COR, COOH, CONHR, CF₃,            Sn(R)₃, or            -   R₃ together with the benzene ring to which it is                attached forms a fused ring system represented by the                structure:

-   -   -   Z is NO₂, CN, Cl, F, Br, I, H, COR, COOH, or CONHR;        -   Y is CF₃, alkoxy, alkyl, hydroxyalkyl, alkylaldehyde,            formyl, H, F, Br, Cl, I, CN, or Sn(R)₃;

    -   Q is H, alkyl, halogen, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂, NHCOCH₃,        NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,        NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OH, OR, COR, OCOR, OSO₂R,        SO₂R, SR; or Q together with the benzene ring to which it is        attached is a fused ring system represented by structure A, B or        C:

-   -   -   n is an integer of 1-4; and        -   m is an integer of 1-3;

    -   or an isomer, pharmaceutically acceptable salt, pharmaceutical        product, N-oxide, hydrate thereof or any combination thereof.

In one embodiment, the present invention provides, a feed compositionfor an animal comprising a compound of formula IIIA:

whereinZ is NO₂, CN, Cl, F, Br, I, H, COR, COOH, or CONHR;Y is CF₃, alkoxy, alkyl, hydroxyalkyl, alkylaldehyde, formyl, H, F, Br,Cl, I, CN, or Sn(R)₃;R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, halogen, alkenyl or OH;R₂ is H, F, Cl, Br, I, CH₃, CF₃, OH, CN, NO₂, NHCOCH₃, NHCOCF₃, NHCOR,alkyl, arylalkyl, OR, NH₂, NHR, N(R)₂, SR;R₃ is H, F, Cl, Br, I, CN, NO₂, COR, COOH, CONHR, CF₃, Sn(R)₃;Q is H, alkyl, halogen, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃,NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR,NHSO₂CH₃, NHSO₂R, OH, OR, COR, OCOR, OSO₂R, SO₂R, SR;n is an integer of 1-4; andm is an integer of 1-3;or its isomer, pharmaceutically acceptable salt, crystal, N-oxide,hydrate or any combination thereof to said subject.

In one embodiment, the present invention provides a compound of formulaIII wherein X is O. In another embodiment, the present inventionprovides a compound of formula III wherein T is OH. In anotherembodiment, the present invention provides a compound of formula IIIwherein R₁ is CH₃. In another embodiment, the present invention providesa compound of formula III or IIIA wherein Z is CN. In anotherembodiment, the present invention provides a compound of formula III orIIIA wherein Z is F. In another embodiment, the present inventionprovides a compound of formula III or IIIA wherein Z is NO₂. In anotherembodiment, the present invention provides a compound of formula III orIIIA, wherein Y is CH₃. In another embodiment, the present inventionprovides a compound of formula III or IIIA, wherein Y is H. In anotherembodiment, the present invention provides a compound of formula III orIIIA wherein Y is CF₃. In another embodiment, the present inventionprovides a compound of formula III or IIIA, wherein Y is Cl. In anotherembodiment, the present invention provides a compound of formula III orIIIA wherein R₃ is H and none of Y, Z, Q or R₂ are H. In anotherembodiment, the present invention provides a compound of formula III orIIIA wherein R₃ is CN. In another embodiment, the present inventionprovides a compound of formula III or IIIA wherein R₃ is Cl. In anotherembodiment, the present invention provides a compound of formula III orIIIA wherein R₃ is F. In another embodiment, the present inventionprovides a compound of formula III or IIIA wherein Q is CN. In anotherembodiment, the present invention provides a compound of formula III orIIIA wherein Q is F. In another embodiment, the present inventionprovides a compound of formula III or IIIA wherein Q is Cl. In anotherembodiment, if R₃ of formula III or IIIA is H, then none of Z or Y or R₂or Q are H.

In one embodiment, the present invention provides a compoundcharacterized by the structure of formula IV:

wherein R₃, m and n are as described for the structure of formula III.

In one embodiment, this invention provides a compound of formulaS-XXIII:

In one embodiment, this invention provides a compound of formula

In one embodiment, this invention provides a compound of formula XXV:

In one embodiment, this invention provides an analog of the compound offormulas I-XXV. In another embodiment, this invention provides aderivative of the compound of formulas I-XXV. In another embodiment,this invention provides a prodrug of the compound of formulas I-XXV. Inanother embodiment, this invention provides a metabolite of the compoundof formulas I-XXV. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formulas I-XXV. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound to of formulas I-XXV. In another embodiment, this inventionprovides a hydrate of the compound of formulas I-XXV. In anotherembodiment, this invention provides an N-oxide of the compound offormulas I-XXV. In another embodiment, this invention provides apolymorph of the compound of formulas I-XXV. In another embodiment, thisinvention provides a crystal of the compound of formulas I-XXV. Inanother embodiment, this invention provides an impurity of the compoundof formulas I-XXV. In another embodiment, this invention provides acombination of any of an analog, derivative, metabolite, isomer,prodrug, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, hydrate, N-oxide of the compound offormulas I-XXV.

As contemplated herein, the present invention relates to the use of aSARM compound and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, polymorph, crystal, impurity or combinations thereof. In oneembodiment, the invention relates to the use of an analog of the SARMcompound. In another embodiment, the invention relates to the use of aderivative of the SARM compound. In another embodiment, the inventionrelates to the use of an isomer of the SARM compound. In anotherembodiment, the invention relates to the use of a metabolite of the SARMcompound. In another embodiment, the invention relates to the use of apharmaceutically acceptable salt of the SARM compound. In anotherembodiment, the invention relates to the use of a pharmaceutical productof the SARM compound. In another embodiment, the invention relates tothe use of a hydrate of the SARM compound. In another embodiment, theinvention relates to the use of an N-oxide of the SARM compound. Inanother embodiment, the invention relates to the use of a polymorph ofthe SARM compound. In another embodiment, the invention relates to theuse of a crystal of the SARM compound. In another embodiment, theinvention relates to the use of an impurity of the SARM compound.

As defined herein, the term “isomer” includes, but is not limited to,optical isomers and analogs, structural isomers and analogs,conformational isomers and analogs, and the like. In one embodiment, theterm “isomer” is meant to encompass optical isomers of the SARMcompound. It will be appreciated by those skilled in the art that theSARMs of the present invention contain at least one chiral center.Accordingly, the SARMs used in the methods of the present invention mayexist in, and be isolated in, optically-active or racemic forms. Somecompounds may also exhibit polymorphism. It is to be understood that thepresent invention encompasses any racemic, optically-active,polymorphic, or stereroisomeric form, or mixtures thereof, which formpossesses properties useful in the treatment of androgen-relatedconditions described herein. In one embodiment, the SARMs are the pure(R)-isomers. In another embodiment, the SARMs are the pure (S)-isomers.In another embodiment, the SARMs are a mixture of the (R) and the (S)isomers. In another embodiment, the SARMs are a racemic mixturecomprising an equal amount of the (R) and the (S) isomers. It is wellknown in the art how to prepare optically-active forms (for example, byresolution of the racemic form by recrystallization techniques, bysynthesis from optically-active starting materials, by chiral synthesis,or by chromatographic separation using a chiral stationary phase).

In one embodiment, this invention encompasses the use of various opticalisomers of the SARM compound. It will be appreciated by those skilled inthe art that the SARMs of the present invention contain at least onechiral center. Accordingly, the SARMs used in the methods of the presentinvention may exist in, and be isolated in, optically-active or racemicforms. Some compounds may also exhibit polymorphism. It is to beunderstood that the present invention encompasses any racemic,optically-active, polymorphic, or stereroisomeric form, or mixturesthereof, which form possesses properties useful in the treatment ofandrogen-related conditions described herein. In one embodiment, theSARMs are the pure (R)-isomers. In another embodiment, the SARMs are thepure (S)-isomers. In another embodiment, the SARMs are a mixture of the(R) and the (S) isomers. In another embodiment, the SARMs are a racemicmixture comprising an equal amount of the (R) and the (S) isomers. It iswell known in the art how to prepare optically-active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase).

The invention includes “pharmaceutically acceptable salts” of thecompounds of this invention, which may be produced, by reaction of acompound of this invention with an acid or base.

Suitable pharmaceutically-acceptable salts of amines of formulas I-XXVmay be prepared from an inorganic acid or from an organic acid. In oneembodiment, examples of inorganic salts of amines are bisulfates,borates, bromides, chlorides, hemisulfates, hydrobromates,hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates),iodates, iodides, isothionates, nitrate, persulfates, phosphate,sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates,arylsulfonates, halogen substituted alkylsulfonates, halogen substitutedarylsulfonates), sulfonates and thiocyanates.

In one embodiment, examples of organic salts of amines may be selectedfrom aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areacetates, arginines, aspartates, ascorbates, adipates, anthranilate,algenate, alkane carboxylates, substituted alkane carboxylates,alginates, benzenesulfonates, benzoates, bisulfates, butyrates,bicarbonates, bitartrates, carboxilate, citrates, camphorates,camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates,calcium edetates, camsylates, carbonates, clavulanates, cinnamates,dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides,decanoates, enanthuates, ethanesulfonates, edetates, edisylates,estolates, esylates, fumarates, formates, fluorides, galacturonategluconates, glutamates, glycolates, glucorate, glucoheptanoates,glycerophosphates, gluceptates, glycollylarsanilates, glutarates,glutamate, heptanoates, hexanoates, hydroxymaleates, hydroxycarboxlicacids, hexylresorcinates, hydroxybenzoates, hydroxynaphthoate,hydrofluorate, lactates, lactobionates, laurates, malates, maleates,methylenebis(beta-oxynaphthoate), malonates, mandelates, mesylates,methane sulfonates, methylbromides, methylnitrates, methylsulfonates,monopotassium maleates, mucates, monocarboxylates, nitrates,naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, napsylates,N-methylglucamines, oxalates, octanoates, oleates, pamoates,phenylacetates, picrates, phenylbenzoates, pivalates, propionates,phthalates, phenylacetate, pectinates, phenylpropionates, palmitates,pantothenates, polygalacturates, pyruvates, quinates, salicylates,succinates, stearates, sulfanilate, subacetates, tartarates,theophyllineacetates, p-toluenesulfonates (tosylates),trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates,triethiodide, tricarboxylates, undecanoates and valerates.

In one embodiment, examples of inorganic salts of carboxylic acids orphenols may be selected from ammonium, alkali metals to include lithium,sodium, potassium, cesium; alkaline earth metals to include calcium,magnesium, aluminium; zinc, barium, cholines, quaternary ammoniums.

In another embodiment, examples of organic salts of carboxylic acids orphenols may be selected from arginine, organic amines to includealiphatic organic amines, alicyclic organic amines, aromatic organicamines, benzathines, t-butylamines, benethamines(N-benzylphenethylamine), dicyclohexylamines, dimethylamines,diethanolamines, ethanolamines, ethylenediamines, hydrabamines,imidazoles, lysines, methylamines, meglamines, N-methyl-D-glucamines,N,N-dibenzylethylenediamines, nicotinamides, organic amines, ornithines,pyridines, picolies, piperazines, procain,tris(hydroxymethyl)methylamines, triethylamines, triethanolamines,trimethylamines, tromethamines and ureas.

In one embodiment, the salts may be formed by conventional means, suchis as by reacting the free base or free acid form of the product withone or more equivalents of the appropriate acid or base in a solvent ormedium in which the salt is insoluble or in a solvent such as water,which is removed in vacuo or by freeze drying or by exchanging the ionsof a existing salt for another ion or suitable ion-exchange resin.

In one embodiment, the invention also includes N-oxides of the aminosubstituents of the compounds described herein. Also, esters of thephenolic compounds can be made with aliphatic and aromatic carboxylicacids, for example, acetic acid and benzoic acid esters.

This invention provides derivatives of the SARM compounds. In oneembodiment, “derivatives” includes but is not limited to etherderivatives, acid derivatives, amide derivatives, ester derivatives andthe like. In another embodiment, this invention further includeshydrates of the SARM compounds.

In one embodiment, “hydrate” includes but is not limited to hemihydrate,monohydrate, dihydrate, trihydrate and the like.

This invention provides, in other embodiments, metabolites of the SARMcompounds. In one embodiment, “metabolite” means any substance producedfrom another substance by metabolism or a metabolic process.

This invention provides, in other embodiments, pharmaceutical productsof the SARM compounds. The term “pharmaceutical product” refers, inother embodiments, to a composition suitable for pharmaceutical use(pharmaceutical composition), for example, as described herein.

An “alkyl” group refers, in one embodiment, to a saturated aliphatichydrocarbon, including straight-chain, branched-chain and cyclic alkylgroups. In one embodiment, the alkyl group has 1-12 carbons. In anotherembodiment, the alkyl group has 1-7 carbons. In another embodiment, thealkyl group has 1-6 carbons. In another embodiment, the alkyl group has1-4 carbons. The alkyl group may be unsubstituted or to substituted byone or more groups selected from halogen, hydroxy, alkoxy carbonyl,amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino,carboxyl, thio and thioalkyl. In one embodiment, the alkyl group is CH₃.

An “alkenyl” group refers, in another embodiment, to an unsaturatedhydrocarbon, including straight chain, branched chain and cyclic groupshaving one or is more double bond. The alkenyl group may have one doublebond, two double bonds, three double bonds etc. Examples of alkenylgroups are ethenyl, propenyl, butenyl, cyclohexenyl etc. In oneembodiment, the alkylene group has 1-12 carbons. In another embodiment,the alkylene group has 1-7 carbons. In another embodiment, the alkylenegroup has 1-6 carbons. In another embodiment, the alkylene group has 1-4carbons. The alkenyl group may be unsubstituted or substituted by one ormore groups selected from halogen, hydroxy, alkoxy carbonyl, amido,alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino,carboxyl, thio and thioalkyl.

A “haloalkyl” group refers to an alkyl group as defined above, which issubstituted by one or more halogen atoms, in one embodiment by F, inanother embodiment by Cl, in another embodiment by Br, in anotherembodiment by I.

An “aryl” group refers to an aromatic group having at least onecarbocyclic aromatic group or heterocyclic aromatic group, which may beunsubstituted or substituted by one or more groups selected fromhalogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido,dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy or thio orthioalkyl. Nonlimiting examples of aryl rings are phenyl, naphthyl,pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl,furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like. Inone embodiment, the aryl group is a 4-8 membered ring. In anotherembodiment, the aryl group is a 4-12 membered ring(s). In anotherembodiment, the aryl group is a 6 membered ring. In another embodiment,the aryl group is a 5 membered ring. In another embodiment, the arylgroup is 2-4 fused ring system.

A “hydroxyl” group refers to an OH group. It is understood by a personskilled in the art that when T is OR, R is not OH.

In one embodiment, the term “halogen refers to in one embodiment to F,in another embodiment to Cl, in another embodiment to Br, in anotherembodiment to I.

An “arylalkyl” group refers, in another embodiment, to an alkyl bound toan aryl, wherein alkyl and aryl are as defined above. An example of anarylalkyl group is a benzyl group.

In another embodiment, the present invention provides process forpreparing a selective androgen receptor modulator (SARM) compoundrepresented by the structure of formula III:

wherein

-   -   X is a bond, O, CH₂, NH, Se, PR, NO or NR;    -   G is O or S;    -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is H, F, Cl, Br, I, CH₃, CF₃, OH, CN, NO₂, NHCOCH₃, NHCOCF₃,        NHCOR, alkyl, arylalkyl, OR, NH₂, NHR, N(R)₂, SR;    -   R₃ is H, F, Cl, Br, I, CN, NO₂, COR, COOH, CONHR, CF₃, Sn(R)₃,        or        -   R₃ together with the benzene ring to which it is attached            forms a fused ring system represented by the structure:

-   -   Z is NO₂, CN, Cl, F, Br, I, H, COR, COOH, or CONHR;    -   Y is CF₃, alkoxy, alkyl, hydroxyalkyl, alkylaldehyde, formyl, H,        F, Br, Cl, I, CN, or Sn(R)₃;    -   Q is H, alkyl, halogen, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂, NHCOCH₃,        NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,        NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OH, OR, COR, OCOR, OSO₂R,        SO₂R, SR; or Q together with the benzene ring to which it is        attached is a fused ring system represented by structure A, B or        C:

-   -   n is an integer of 1-4; and    -   m is an integer of 1-3;

the process comprising the step of coupling a compound of formula (10):

wherein Z, Y, G, R₁, T, R₃ and m are as defined above and L is a leavinggroup, with a compound of formula II:

wherein Q, X, R₂ and n are as defined above.

In one embodiment, the coupling step is carried out in the presence of abase. In another embodiment, the leaving group L is Br.

In another embodiment, the compound of formula 10 is prepared by:

a) preparing a compound of formula 13 by ring opening of a cycliccompound of formula 12:

wherein L, R₁, G and T are as defined above, and T₁ is O or NH; and

b) reacting an amine of formula 14:

wherein Z, Y, R₃ and m are as defined above, with the compound offormula 13, in the presence of a coupling reagent, to produce thecompound of formula 10.

It is understood to a person skilled in the art that when T₁ is O or NH,T in compound 13 is O or NH₂. Thus, when T in compound 13 is OR, thereaction will involve a further step of converting the OH to OR by areaction with, for example, an alkyl halide R—X. When T in compound 13is NHCOR, NHCOCH₃, the reaction will involve a further step ofconverting the NH₂ to NHCOR or NHCOCH₃, by a reaction with, for example,the corresponding acyl chloride ClCOR or ClCOCH₃.

In one embodiment, step (a) is carried out in the presence of HBr.

In one embodiment, whereby compound 13 of step (a) is reacted with acoupling agent prior to step (b).

In one embodiment, the coupling step is carried out in the presence of abase. In another embodiment, the leaving group L is Br.

In another embodiment, the process further comprises the step ofconverting the selective androgen receptor modulator (SARM) compound toits analog, isomer, metabolite, derivative, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, N-oxide,hydrate or any combination thereof.

In another embodiment, this invention provides a large scale process forthe preparation of compound of formula III, wherein the processcomprises the same steps as described herein above, wherein compound offormula 12 is prepared according to the following scheme, in thepresence of 4N NaOH:

FIGS. 1K and 1L provide one embodiment of a large scale process for thepreparation of a large scale synthesis of compounds of formulas S-II.

In one embodiment, the present invention provides a process forpreparing a compound of formula III wherein is X is O. In anotherembodiment, the present invention provides a process for preparing acompound of formula III wherein T is OH. In another embodiment, thepresent invention provides a process for preparing a compound of formulaIII wherein is R₁ is CH₃. In another embodiment, the present inventionprovides a process for preparing a compound of formula III wherein Z isCN, and/or Cl and/or F. In another embodiment, the present inventionprovides a process for preparing a compound of formula III, wherein Z isCN. In another embodiment, the present invention provides a process forpreparing a compound of formula III wherein Y is CF₃ and/or CH₃, and/orH and/or Cl. In another embodiment, the present invention provides aprocess for preparing a compound of formula III wherein R₃ is H, and/orCN, and/or Cl and/or F. In another embodiment, the present inventionprovides a process for preparing a compound of formula III wherein Q isCN. In another embodiment, the present invention provides a process forpreparing a compound of formula III wherein Q is F. In anotherembodiment, the present invention provides a process for preparing acompound of formula III wherein Q is Cl.

In another embodiment, the present invention provides a process forpreparing a selective androgen modulator compound represented by thestructure of formula II, as depicted in FIG. 1 and Example 1:

In another embodiment, the present invention provides a process forpreparing an (S) enantiomer of SARM compound represented by thestructure of formula S-II:

said process comprising the steps of:a) coupling an amine of formula 17:

with the carboxylic acid of formula R-18

in the presence of a coupling reagent, to produce an amide of formulaR-19

andb) reacting the amide of formula R-19 with a compound of formula 20:

to produce a compound of formula S-II.

In one embodiment, whereby compound R-18 of step (a) is reacted with acoupling agent prior to addition of compound of formula 17.

FIG. 1A and Example 1 provide one embodiment of a process for thepreparation of a compound of formula S-II.

In another embodiment, the conditions of step (b) of the processoutlined hereinabove may comprise potassium carbonate, sodium carbonate,or cesium carbonate, or another base appropriate for this reaction,using 2-propanol, THF or methylethylketone as a solvent, optionally witha transition catalyst, BTBAC (benzyltributylammonium chloride) or othersuitable agent.

In another embodiment, the present invention provides a process forpreparing an (R) enantiomer of SARM compound represented by thestructure of formula R-II:

said process comprising the steps of:

a) coupling an amine of formula 17:

with the carboxylic acid of formula 5-18

in the presence of a coupling reagent, to produce an amide of formula5-19

andb) reacting the amide of formula 5-19 with a compound of formula 20

to produce a compound of R-II.

In one embodiment, whereby compound 5-18 of step (a) is reacted with acoupling agent prior to addition of compound of formula 17.

FIG. 1B depicts one embodiment of such a process for the preparation ofcompound of formula R-II.

In another embodiment, the conditions of step (b) of the processoutlined hereinabove may comprise potassium carbonate, sodium carbonate,or cesium carbonate, or another base appropriate for this reaction,using 2-propanol, THF or methylethylketone as a solvent, optionally witha transition catalyst, BTBAC (benzyltributylammonium chloride) or othersuitable agent.

In another embodiment, the present invention provides a process forpreparing an (S) enantiomer of a SARM compound represented by thestructure of formula S-II

said process comprising the steps of:

a) coupling an amine of formula 17:

with the carboxylic acid of formula R-18

in the presence of a coupling reagent, to produce an amide of formulaR-19

b) reacting the amide of formula R-19, with a base to form an oxiraneS-21

andc) reacting the oxirane of formula 5-21 with a compound of formula 20:

to produce a compound of S-II.

In one embodiment, whereby compound R-18 of step (a) is reacted with acoupling agent prior addition of compound of formula 17.

FIG. 10 depicts an embodiment of such a process for the preparation ofcompound of formula S-II.

In another embodiment, the present invention provides a process forpreparing an (R) enantiomer of SARM compound represented by thestructure of formula R-II:

said process comprising the steps of:

a) coupling an amine of formula 17:

with the carboxylic acid of formula S-18

in the presence of a coupling reagent, to produce an amide of formulaS-19

b) reacting the amide of formula S-19, with a base to form an oxiraneR-21

c) reacting the oxirane of formula R-21 with a compound of formula 20;

to produce a compound of R-II.

In one embodiment, whereby compound 5-18 of step (a) is reacted with acoupling agent prior to addition of compound of formula 17.

FIG. 1D preparation of compound of formula R-II.

In another embodiment, the present invention provides a process forpreparing an (S) enantiomer of a SARM compound represented by thestructure of formula S-II.

said process comprising the steps of:

a) reacting a ring of formula S-22

with a compound of 20

to produce a compound of formula R-23;

a) ring opening of compound of formula R-23 to produce a compound offormula S-24

andcoupling the carboxylic acid of compound of formula S-24 with the amineof formula 17

to produce the compound of formula S-II.

FIG. 1E depicts an embodiment of such a process for the preparation ofcompound of formula S-II.

In another embodiment, the present invention provides a process forpreparing an (R) enantiomer of a SARM compound represented by thestructure of formula R-II:

said process comprising the steps of:

a) reacting a ring of formula R-22

with a compound of 20

to produce a compound of formula S-23;

b) ring opening of compound of formula S-23 to produce a compound offormula R-24

andcoupling the carboxylic acid of compound of formula R-24 with the amineof formula 17

to produce the compound of formula R-II.

FIG. 1F depicts an embodiment of such a process for the preparation ofcompound of formula R-II.

In another embodiment, the present invention provides a process forpreparing an (S) enantiomer of a SARM compound represented by thestructure of formula S-II

said process comprising the steps of:

a) reacting the carboxylic acid of formula R-18

with tribromoacetaldehyde to produce a compound of formula R-25:

reacting the dioxalane derivative R-25 with a compound of formula 20

to produce a compound of formula R-26;

b) ring opening of compound of formula R-26 to produce a compound offormula S-24

andcoupling the carboxylic acid of compound of formula S-24 with the amineof formula 17:

to produce the compound of formula S-II.

FIG. 1G depicts an embodiment of such a process for the preparation ofcompound of formula S-II.

In another embodiment, the present invention provides a process forpreparing an (R) enantiomer of a SARM compound represented by thestructure of formula R-II

said process comprising the steps of:

a) reacting the carboxylic acid of formula S-18

with tribromoacetaldehyde to produce a compound of formula S-25:

reacting the dioxalane derivative S-25 with a compound of formula 20

to produce a compound of formula S-26;

ring opening of compound of formula S-26 to produce a compound offormula R-24

andcoupling the carboxylic acid of compound of formula R-24 with the amineof formula 17:

to produce the compound of formula R-II.

FIG. 1H depicts an embodiment of such a process for the preparation ofcompound of formula R-II.

In another embodiment, the present invention provides a process forpreparing a racemic mixture of a SARM compound represented by thestructure of formula II

is said process comprising the steps of:

a) reacting a compound of formula 24

with a compound of formula 27

wherein P is selected from isocyanate (NCO) or isothiocyanate (NCS) toproduce a compound of formula 28a or 28b, respectively

b) ring opening of the oxazolidinedione or 2-thioxooxazolid-4-one ringof formula 28a or 28b in a presence of a base to produce a compound offormula II.

FIG. 1I depicts an embodiment of such a process for the preparation ofracemic compound of formula II.

In another embodiment, the present invention provides a process forpreparing a racemic mixture of a SARM compound represented by thestructure of to formula II:

said process comprising the steps of:

a) chlorinating methacrylic acid:

b) coupling an 3-cyano 4-trifluoromethyl aniline of formula 17 withmethacryloyl chloride:

to produce the amide of formula 29,

c) oxidizing an amide of formula 29, to produce the oxirane of formula21:

andd) reacting the oxirane of formula 21 with a compound of formula 20:

to produce the compound.

In another embodiment, the oxidizing an amide of formula 29 of step (c)to comprises ozone. In another embodiment, the oxidizing agent is aperoxyacid, for example, peracetic acid, (CH₃COOOH). In anotherembodiment, the oxidizing agent meta-chloroperbenzoic acid (m-CPBA). Inanother embodiment, the oxidizing agent is magnesium monoperoxypthalicacid (MMPP). In another embodiment, the oxidizing agent is hydrogenperoxide together with catalytic amounts (1.0-0.1 mol %) of manganese(2⁺) salts.

FIG. 1J depicts an embodiment of a process for the preparation ofracemic compound of formula II.

In one embodiment, this invention provides a process for preparing pureenantiomers of SARMs compounds of this invention, comprising the stepsof a) preparing a racemic SARM compound of this invention; and b)separating pure SARM compound of this invention from its racemicmixture.

In one embodiment, separation of the optically-active (R) isomer or (S)enantiomer, from the racemic SARM compounds of this invention comprisescrystallization techniques. In another embodiment, the crystallizationtechniques include differential crystallization of enantiomers. Inanother embodiment, the crystallization techniques include differentialcrystallization of diastereomeric salts (tartaric salts or quininesalts). In another embodiment, the crystallization techniques includedifferential crystallization of chiral auxiliary derivatives (mentholesters, etc). In another embodiment, separation of the optically-active(R) isomer or (S) enantiomer, from the racemic SARM compounds of thisinvention comprises reacting the racemate mixture with another chiralgroup, forming of a diastereomeric mixture followed by separation of thediastereomers and removing the additional chiral group to obtain pureenantiomers. In another embodiment, separation of the optically-active(R) isomer or (S) enantiomer, from the racemic SARM compounds of thisinvention comprises chiral synthesis. In another embodiment, separationof the optically-active (R) isomer or (S) enantiomer, from the racemicSARM compounds of this invention comprises biological resolution. Inanother embodiment, separation of the optically-active (R) isomer or (S)enantiomer, from the racemic SARM compounds of this invention comprisesenzymatic resolution. In another embodiment, separation of theoptically-active (R) isomer or (S) enantiomer, from the racemic SARMcompounds of this invention comprises chromatographic separation using achiral stationary phase. In another embodiment, separation of theoptically-active (R) isomer or (S) enantiomer, from the racemic SARMcompounds of this invention comprises affinity chromatography. Inanother embodiment, separation of the optically-active (R) isomer is or(S) enantiomer, from the racemic SARM compounds of this inventioncomprises capillary electrophoresis. In another embodiment, separationof the optically-active (R) isomer or (S) enantiomer, from the racemicSARM compounds of this invention comprises forming an ester group of thehydroxyl group of the chiral carbon with an optically-active acid, forexample (−)-camphanic acid, separating the diastereomers esters, thusobtained, by fractional crystallization or preferably, byflash-chromatography, and then hydrolyzing each separate ester to thealcohol.

In another embodiment, the purity, and selectivity of an enantiomerobtained by the process of this invention, or by chiral separation of aracemic mixture of this invention can be determined by HPLC analysis.

In another embodiment, the process further comprises the step ofconverting the SARM compound to its analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,N-oxide, hydrate or any combination thereof.

According to this aspect of the invention, and in one embodiment, thereagent used for reacting the amide derivative, for example compound offormula 19 and the phenol derivative such as for example 20 are carriedout in the presence of a base. Any suitable base that will deprotonatethe hydrogen of the —XH moiety (for example, a phenol moiety when X isO) and allow the coupling may be used. Nonlimiting examples of bases arecarbonates such as alkali carbonates, for example sodium carbonate(Na₂CO₃), potassium carbonate (K₂CO₃) and cesium carbonate (Cs₂CO₃);bicarbonates such as alkali metal bicarbonates, for example sodiumbicarbonate (NaHCO₃), potassium bicarbonate (KHCO₃), alkali metalhydrides such as sodium hydride (NaH), potassium hydride (KH) andlithium hydride (LiH), and the like.

The leaving group L, according to this aspect, and in one embodiment,may comprise any removable group customarily considered for chemicalreactions, as will be known to the person skilled in the art. Suitableleaving groups are halogens, for example F, Cl, Br and I; alkylsulfonate esters (—OSO₂R) wherein R is an alkyl group, for examplemethanesulfonate (mesylate), trifluoromethanesulfonate, ethanesulfonate,2,2,2-trifluoroethanesulfonate, perfluoro butanesulfonate; arylsulfonate esters (—OSO₂Ar) wherein Ar is an aryl group, for examplep-toluoylsulfonate (tosylate), benzenesulphonate which may beunsubstituted or substituted by methyl, chlorine, bromine, nitro and thelike; NO₃, NO₂, or sulfate, sulfite, phosphate, phosphite, carboxylate,imino ester, N₂ or carbamate.

According to this aspect of the invention and in one embodiment, thereaction is carried out in a suitable inert solvent or diluent such as,for example, tetrahydrofuran, diethyl ether, acetone, methyl ethylketone, 2-propanol, aromatic amines such as pyridine; aliphatic andaromatic hydrocarbons such as benzene, toluene, and xylene;dimethylsulfoxide (DMSO), dimethylformamide (DMF), and dimethylacetamide(DMAC). In one embodiment, the reaction may be carried out in a suitableinert solvent or diluent as described hereinabove, suitably in thepresence of a base such as triethylamine, and at a temperature in therange, as described above. In one embodiment, the reaction may becarried out at an appropriate temperature, as will be known to oneskilled in the art, for example, in the range, of −20 to 120° C., or forexample at or near ambient temperature.

The coupling reagent defined hereinabove is a reagent capable of turningthe carboxylic acid/thiocarboxylic acid of formula 24 or 18 into areactive derivative thereof, thus enabling coupling with the respectiveamine to form an amide/thioamide bond. A suitable reactive derivative ofa carboxylic acid/thiocarboxylic acid is, for example, an acylhalide/thioacyl halide, for example an acyl/thioacyl chloride formed bythe reaction of the acid/thioacid and an inorganic acid chloride, forexample thionyl chloride; a mixed anhydride, for example an anhydrideformed by the reaction of the acid and a chloroformate such as isobutylchloroformate; an active ester/thioester, for example an ester formed bythe reaction of the acid and a phenol such as pentafluorophenol, anester such as pentafluorophenyl trifluoroacetate or an alcohol such asmethanol, ethanol, isopropanol, butanol or N-hydroxybenzotriazole; anacyl/thioacyl azide, for example an azide formed by the reaction of theacid/thioacid and azide such as diphenylphosphoryl azide; an acylcyanide/thioacyl cyanide, for example a cyanide formed by the reactionof an acid and a cyanide such as diethylphosphoryl cyanide; or theproduct of the reaction of the acid/thioacid and a carbodiimide such asdicyclohexylcarbodiimide.

It is to be understood that the process may comprise any embodimentdescribed herein, as will be appropriate to produce a SARM of acorresponding formula, as will be appreciated by one skilled in the art.

In one embodiment, the process for preparing a SARM of this inventionmay involve ring opening in the presence of less acidic conditions,which in another embodiment, diminish the likelihood of obtaining SARMcompound mixtures, and provide higher yield and purity of a SARM ofinterest. In one embodiment, the ring opening of a process as describedherein, to produce a carboxylic acid of formula 13, is carried out inthe presence of HBr, which, in one embodiment, is at a concentration ofup to 30%, or in another embodiment, of up to 40%, or in anotherembodiment, is of up to 25%, or in another embodiment, of up to 23%, orin another embodiment, of up to between 20-25%. In one embodiment, theSARMs of this invention may be produced via large-scale synthesis,providing highly pure products in high yields.

In one embodiment, the reaction may be carried out in a suitable inertsolvent or diluent as described hereinabove, suitably in the presence ofa base such as triethylamine, and at a temperature in the range, asdescribed above.

In some embodiments the compounds for use in the methods of thisinvention are nonsteroidal ligands for the androgen receptor and maydemonstrate tissue-selective androgenic and/or anabolic activity. Thesenovel agents are useful in affecting the carcass composition, increasingthe lean mass and/or reducing the fat mass of an animal, reducingpercent fat mass, increasing feed efficiency, increasing average dailygain (ADG), decreasing feed to gain ratio (F:G), increasing musclegrowth, modulation of meat quality, and/or enhancing productive life ofanimals, including feedlot animals, beef cattle and finishing livestock.These novel agents are useful in males for the treatment of a variety ofhormone-related conditions such as sexual dysfunction, decreased sexuallibido, erectile dysfunction, hypogonadism, sarcopenia, osteopenia,osteoporosis, alterations in cognition and mood, depression, anemia,hair loss, obesity, benign prostate hyperplasia and/or prostate cancer.Further, the compounds are useful as adjunct to androgen-deprivationtherapy (ADT) for treating prostate cancer. Further, the compounds areuseful for oral testosterone replacement therapy, and treating prostatecancer. In other embodiments, the compounds are useful for the treatmentof a variety of hormone-related conditions in females including, sexualdysfunction, decreased sexual libido, hypogonadism, sarcopenia,osteopenia, osteoporosis, alterations in cognition and mood, depression,anemia, hair loss, obesity, endometriosis, infertility, breast cancer,uterine cancer and ovarian cancer. In other embodiments, the SARMs areuseful for treating, suppressing, inhibiting or reducing the incidenceof diabetes type II, diabetes type I, glucose intolerance,hyperinsulinemia, insulin resistance, dyslipidemia,hypercholesterolemia, high blood pressure, obesity, fatty liverconditions, diabetic nephropathy, diabetic neuropathy, diabeticretinopathy, cardiovascular disease, atherosclerosis, cerebrovascularconditions and stroke.

In some embodiments, the compounds as described herein are useful inpreventing and treating muscle wasting disorders, bone relateddisorders, and diabetes is related disorders.

In some embodiments, the compounds as described herein are useful,either alone or as a combination with beta-agonists as feed composition,pharmaceutical compositions or as methods for affecting the carcasscomposition, increasing the lean mass, reducing the fat mass and/orreducing the percent fat mass, increasing feed efficiency, increasingaverage daily gain (ADG), decreasing feed to gain ratio (F:G) of ananimal. In some embodiment, the compounds as described herein areuseful, either alone or as a combination with beta-agonists as feedcomposition or as methods for increasing the muscle growth of an animal,decreasing time to market (or time to slaughter), increasing carcassweight (or slaughter weight) of a feedlot or finishing animal,modulation of meat quality, enhancing productive life of and/orimproving herd health of animals, including feedlot animals, beef cattleand finishing livestock.

In some embodiments, the compounds as described herein are useful,either alone or as a composition, in males and females for the treatmentof a variety of hormone-related conditions, such as hypogonadism,sarcopenia, erectile dysfunction, lack of libido, osteoporosis andfertility. In some embodiments, the compounds as described herein areuseful in stimulating or promoting or restoring function to variousprocesses, which in turn result in the treatment of the conditions asherein described, including, inter aila, promoting erythropoiesis,osteogenesis, muscle growth, glucose uptake, insulin secretion, and/orpreventing lipidogenesis, clotting, insulin resistance, atherosclerosis,osteoclast activity, and others.

In one embodiment, the methods of this invention make use of thedescribed compound contacting or binding a receptor, and therebymediating the described effects. In some embodiments, the receptor is anuclear receptor, which in one embodiment, is an androgen receptor, orin another embodiment, is an estrogen receptor, or in anotherembodiment, is a progesterone receptor, or in another embodiment, is aglucocorticoid receptor. In some embodiments, the multitude of effectsmay occur simultaneously, as a function of binding to multiple receptorsin the subject. In some embodiments, the tissue selective effects of thecompounds as described herein provide for simultaneous action ondifferent target organs.

Compositions and Methods of Use

In some embodiments, this invention provides methods of use which iscomprise administering a composition comprising the described compounds.In one embodiment, a composition is a pharmaceutical composition. In oneembodiment, a composition is a feed composition. In one embodiment, feedcomposition may be a pharmaceutical composition.

As used herein, “pharmaceutical composition” means a “therapeuticallyeffective amount” of the active ingredient, i.e. the compound of formulaIII, together with a pharmaceutically acceptable carrier or diluent. A“feed composition” means an “effective amount”. A “therapeuticallyeffective amount” and/or an “effective amount” as used herein, refers tothat amount which provides a therapeutic effect or effect on the carcassof the animal for a given condition and administration regimen.

In one embodiment, the present invention encompasses incorporating thecompounds into animal feed. In one embodiment, the present inventionencompasses incorporating the compounds into a feed composition. In someembodiments, the compounds/compositions of this invention may beadministered to any animal as herein described, for example to finishinglivestock. Such administration, in some embodiments, is accomplishedvia, inter alia, supplementation in feeds, feed compositions,formulation into feeds, controlled release implants, topical sprays orcreams/ointments, dissolution in drinking water, rumen-stableformulations to include coatings and derivatives, repeated injection,and other means as will be known to the skilled artisan. In oneembodiment, the present invention encompasses incorporating thecompounds into other typical pharmaceutical administration routes andpharmaceutical compositions as described herein.

As used herein, the term “administering” refers to bringing a subject incontact with a compound of the present invention. As used herein,administration can be accomplished in vitro, i.e. in a test tube, or invivo, i.e. in cells or tissues of living organisms, for example humansand/or animals. In one embodiment, the present invention encompassesadministering the compounds of the present invention to a subject.

In one embodiment, the present invention encompasses administering thecompounds of the present invention via implants. In one embodiment,administering the compounds of the present invention is via controlledrelease implants. In another embodiment of the present invention,administering the compounds of the present invention is via topicaladministration. In one embodiment, topical administration is via atopical spray. In one embodiment, topical administration is via a cream.In one embodiment, topical administration is via an ointment. In oneembodiment, compounds and/or compositions of this invention areadministered via an implant to a pig. In one embodiment, compoundsand/or compositions of this invention are administered via topicaladministration to a pig.

In one embodiment, this invention is directed to a feed composition foran animal comprising a compound of this invention. In one embodiment,this invention is directed to a feed composition for an animalcomprising a compound of formula IIIA or its isomer, pharmaceuticallyacceptable salt, crystal, N-oxide, hydrate or any combination thereof.In one embodiment, this invention is directed to a feed composition foran animal comprising a compound of formula I or its isomer,pharmaceutically acceptable salt, crystal, N-oxide, hydrate or anycombination thereof. In one embodiment this invention is directed to afeed composition for an animal comprising a compound of formula II orits isomer, pharmaceutically acceptable salt, crystal, N-oxide, hydrateor any combination thereof. In one embodiment this invention is directedto a feed composition for an animal comprising a compound of formulaXXIII or its isomer, pharmaceutically acceptable salt, crystal, N-oxide,hydrate or any combination thereof. In one embodiment this invention isdirected to a feed composition for an animal comprising a compound offormula XXIV or its isomer, pharmaceutically acceptable salt, crystal,N-oxide, hydrate or any combination thereof. In one embodiment thisinvention is directed to a feed composition for an animal comprising acompound of formula XXV or its isomer, pharmaceutically acceptable salt,crystal, N-oxide, hydrate or any combination thereof.

The feed composition containing the compounds of this invention can beadministered as additives to the animal feed. In one embodiment, theanimal feed including the feed composition of this invention is providedto the animal once a day. In another embodiment twice a day. In anotherembodiment once to five times a day.

In another embodiment, the feed composition comprises between 0.010-50ppm of a compound of this invention. In another embodiment, the feedcomposition comprises 0.01-1 ppm of a compound of this invention. Inanother embodiment, the feed composition comprises 0.10 ppm of acompound of this invention. In another embodiment, the feed compositioncomprises 1 ppm of a compound of this invention. In another embodiment,the feed composition comprises 3 ppm of a compound of this invention. Inanother embodiment, the feed composition comprises 10 ppm of a compoundof this invention. In another embodiment, the feed composition comprises30 ppm of a compound of this invention.

In one embodiment, the animal is fed with the feed composition of thisinvention after it has reached 60 pounds. In one embodiment, the animalis fed with the feed composition of this invention after it has reached50 pounds. In one embodiment, the animal is fed with the feedcomposition of this invention before it has reached 50 pounds.

In one embodiment, the animal is fed with the feed composition of thisinvention for about ten weeks prior to slaughter. In one embodiment, theanimal is fed with the feed composition of this invention for abouttwenty weeks prior to slaughter. In one embodiment, the animal is fedwith the feed composition of this invention for about a year prior toslaughter.

In another embodiment, the feed composition of this invention comprisesa combination of a compound of this invention and a beta-agonist. Inanother embodiment, the feed composition comprises a compound of formulaII and a beta-agonist. In another embodiment, the feed compositioncomprises a compound of formula XXIII and a beta-agonist. In anotherembodiment, the feed composition comprises a compound of formula XXIVand a beta-agonist. In another embodiment, the feed compositioncomprises a compound of formula XXV and a beta-agonist.

In one embodiment, the animal is raised with a beta-agonist enhanceddiet during a first time period of time and later fed in a diet withsubstantially no beta-agonist, but including a compound of thisinvention during a second period of time.

In one embodiment a beta-agonist includes ractopamine hydrochloride(sold under the tradenames Optaflexx or Paylean, e.g. and available fromElanco of Greenfield, Ind.) and zilpaterol hydrochloride (sold under thetradename of Zilmax available from Invervet of Millsboro, Del.). Otheractive isomers of other drugs with beta-adrenergic agonistic properties,include for example hexoprenaline, isoprenaline, riniterol, isoetharine,metaproterenol, reproterenol, cimaterol, procaterol, carbuterol,tulobuterol, pibuterol, mabuterol, bitolterol, clenbuterol, andbambuterol. Also included may be tautomers of beta-agonists that areunder development, such as broxaterol, etanterol, imoxiterol, namiterol,picumeterol, RP 58802, RU 42173 and ZK 90055. Those skilled in the artwill also realize that there are many pharmaceutically acceptable saltforms of these drugs, such as for example sulfate, fumarate,hydrobromide, dihydrochloride, methanesulphonate, hydroxynaphthoate,hydrochloride or where appropriate, one or other of the hydrate formsthereof.

In one embodiment, the feed composition of this invention is prepared asa dry powder or a granulate and added to the animal feed, such as bymixing. Also, other forms of the additive may also be appropriate. Theadditive can be pre-mixed into the feed according to any of the methodsknown to those skilled in the art, or may be mixed or blended into thefeed at the time of feeding.

In one embodiment, this invention is directed to a pharmaceuticalcomposition for an animal comprising a compound of this invention. Inone embodiment, this invention is directed to a pharmaceuticalcomposition for an animal comprising a compound of formula IIIA or itsisomer, pharmaceutically acceptable salt, crystal, N-oxide, hydrate orany combination thereof. In one embodiment, this invention is directedto a pharmaceutical composition for an animal comprising a compound offormula I or its isomer, pharmaceutically acceptable salt, crystal,N-oxide, hydrate or any combination thereof. In one embodiment thisinvention is directed to a pharmaceutical composition for an animalcomprising a compound of formula II or its isomer, pharmaceuticallyacceptable salt, crystal, N-oxide, hydrate or any combination thereof.In one embodiment this invention is directed to a pharmaceuticalcomposition for an animal comprising a compound of formula XXIII or itsisomer, pharmaceutically acceptable salt, crystal, N-oxide, hydrate orany combination thereof. In one embodiment this invention is directed toa pharmaceutical composition for an animal comprising a compound offormula XXIV or its isomer, pharmaceutically acceptable salt, crystal,N-oxide, hydrate or any combination thereof. In one embodiment thisinvention is directed to a pharmaceutical composition for an animalcomprising a compound of formula XXV or its isomer, pharmaceuticallyacceptable salt, crystal, N-oxide, hydrate or any combination thereof.

The pharmaceutical composition containing the compounds of thisinvention can be administered as additives to the animal feed. In oneembodiment, the animal feed including the pharmaceutical composition ofthis invention is provided to the animal once a day. In anotherembodiment twice a day. In another embodiment once to five times a day.

In another embodiment, the pharmaceutical composition comprises between0.010-50 ppm of a compound of this invention. In another embodiment, thepharmaceutical composition comprises 0.01-1 ppm of a compound of thisinvention. In another embodiment, the pharmaceutical compositioncomprises 0.10 ppm of a compound of this invention. In anotherembodiment, the pharmaceutical composition comprises 1 ppm of a compoundof this invention. In another embodiment, the pharmaceutical compositioncomprises 3 ppm of a compound of this invention. In another embodiment,the pharmaceutical composition comprises 10 ppm of a compound of thisinvention. In another embodiment, the pharmaceutical compositioncomprises 30 ppm of a compound of this invention.

In one embodiment, the pharmaceutical composition of this invention isin an amount from about 0.0005% to about 0.1% of the weight of theanimal. In another embodiment, the pharmaceutical composition of thisinvention is in an amount from about 0.005% to about 0.01% of the weightof the animal. In another embodiment, the pharmaceutical composition ofthis invention is in an amount from about 0.01% to about 0.05%.

In one embodiment, the methods of this invention are used in a subject,which is a human. In another embodiment, the subject is a mammal. Inanother embodiment, the subject is an animal. In another embodiment thesubject is an invertebrate. In another embodiment the subject is avertebrate. In another embodiment, the animal is a feedlot animal. Inanother embodiment, the animal is a beef cattle. In another embodiment,the animal is a finishing livestock.

For administration to mammals, and particularly humans, it is expectedthat the physician will determine the actual dosage and duration oftreatment, which will be most suitable for an individual and can varywith the age, weight and response of the particular individual.

For administration to mammals, in some embodiments, the presentinvention provides compounds, compositions and methods of use thereoffor the enhanced meat productivity in food animals. In some embodiments,this invention provides compounds, compositions and methods of usethereof for the modulation of appetite for feedlot animals. In someembodiments, this invention provides compounds, compositions and methodsof use thereof for improved feed efficiency.

For administration to mammals, in some embodiments, this inventionprovides compounds, compositions and methods of use thereof fordecreased time to market for feedlot animals. In some embodiments, thisinvention provides compounds, compositions and methods of use thereoffor increased terminal weight of feedlot animals. In some embodiments,this invention provides compounds, compositions and methods of usethereof for decreased time to terminal weight of feedlot animals. Insome embodiments, this invention provides compounds, compositions andmethods of use thereof for increased lean weight of feedlot animals. Insome embodiments, this invention provides compounds, compositions andmethods of use thereof for decreased body fat weight of feedlot animals.In some embodiments, this invention provides compounds, compositions andmethods of use thereof for decreased percent body fat weight of feedlotanimals. In some embodiments, this invention provides compounds,compositions and methods of use thereof for the modulation of meatquality in feedlot animals. In some embodiments, this invention providescompounds, compositions and methods of use thereof for increased is meatproduction.

In some embodiments, the term “feedlot animals” refers to, inter alia,any animal the meat of which is considered edible in a given culture orcountry. In some embodiments, such term may include without limitationswine (domestic pig, wild boars), bovine (bison, cattle, yaks), cervids(deer, elk, moose), ovine (sheep/lamb), caprine (goats), lagomorphs(rabbit, pika), avian (chicken, turkey, duck, game birds, emu/ostrich),fish (catfish, tilapia, salmon, red drum), shellfish (crustaceans suchas crab, lobster, shrimp; and mollusks such as clams, octopus, squid),roe (caviar), amphibians (frogs, salamanders), reptiles (snakes, turtle,alligator), canids (dog, fox), felines (cat), equines (horse, donkey,zebras), marsupials (kangaroo, opossum), insects (grasshopper, beetles,larvae), primates (gorilla, monkey), rodents (rat, mouse, squirrel,beaver), cetaceans (whale, dolphin), pinnipeds (walrus, seal),miscellaneous (bear, raccoon, elephant) or others as will be appreciatedby one skilled in the art.

In some embodiments, the term “finishing livestock” refers to, interalia, any animal that is normally fattened for the last few monthsbefore processing. In one embodiment, finishing livestock is a beefcattle. In one embodiment, finishing livestock is a pig. In oneembodiment, finishing livestock is a poultry. In one embodiment,finishing livestock is a farmed fish.

In one embodiment, the compounds, compositions or methods of use thereofmay find application in increasing the yield of all retail productsderived from such feedlot animals. For instance, each of the above foodanimals have different types of tissues and preparations thereof such asfor swine: ham, bacon, sausage, pork bellies, pork chop, ribs, brain,chitterling, tripe, tenderloin, etc.

Feedlot practices often include castration in order to better controlthe behavior of feedlot animals and to improve the quality of the meat(more tender, marbled, and colored). This occurs with a loss ofproductivity which could be offset using nonsteroidal androgens,representing one embodiment of a mechanism whereby the compounds andcomposition find application therein.

In some embodiments, enhancing measures of productivity in feedlotanimals may comprise enhancing the number of animals per litter, littersper breeding animal per year, slaughter head count per breeding animalper year, meat product production (in pounds) per breeding animal peryear, average daily growth in pounds, live weight (in pounds), dressingpercent (% of live weight), dressed weight in pounds, retail meat inpounds per head count, retail meat yield (percent of live weight), orany combination thereof.

In one embodiment, the compounds, compositions or methods of use thereofmay find application in stud farm productivity. Androgens (steroidal andnonsteroidal) are known to enhance sex drive in males and females suchthat, in some embodiments, the stud animals are productive in terms of“open” mating time or births per mating event. In some embodiments, thesupport of sex organs and accessory tissues (and health benefits) of thecompounds/compositions of this invention may increase productive life ofa stud animal, allowing him to “stand at stud” (i.e. meaning availablefor reproduction) for a longer period of time. Female receptivity isenhanced, in some embodiments, in terms of frequency, in response tocontact with/administration of a compound/composition of this invention.

In some embodiments, this invention comprises application of any methodas herein described for veterinary use, in any animal as describedherein. In some embodiments, treatment of such conditions or diseases inanimals may find application for pleasure and/or profit animals, mayincrease the size of game animals by supplementation, etc. as will beappreciated by one skilled in the art.

In some embodiments, the compounds/compositions may be administered toany animal as herein described, for example to livestock. Suchadministration, in some embodiments, is accomplished via, inter alia,supplementation in feeds, formulation into feeds, controlled releaseimplants, dissolution in drinking water, rumen-stable formulations toinclude coatings and derivatives, repeated injection, and other means aswill be known to the skilled artisan.

In some embodiments, dosages as described herein for humans will beadjusted to accommodate the varying size of animals. Such modificationof dosage is well known in the field of veterinary art, and is availablein common veterinary manuals, and may vary on a scale ranging frommilligrams to grams as a function of such varying size.

In some embodiments, the compounds/compositions may be administered toany animal as herein described, in combination with any other agent asdescribed herein, befitting the particular animal and condition in theanimal, which is being treated. In some embodiments, such combinationtherapy may comprise administration of the compounds/compositions withhigh fat diets such as supplemented with fatty acids or oils to improvethe meat quality; various combinations with androgens, progestins,anti-glucocorticoids, estrogens, growth hormone, etc. can be tailored toproduce maximum weight gain performance in different types of animals(cows vs. pigs; intact vs. castrated) the specifics of which are knownby those skilled in the art (see for example, Environ Qual Saf Suppl.1976; (5):89-98).

In some embodiments, the compounds/compositions may be administered toany animal as herein described, which is a food source for humans, andin some embodiments, the tissue-selectivity and shorter half-lives ofthe compounds as herein described significantly lowers anticipatedenvironmental effects. In some embodiments, the risk to humanconsumption thereby, as compared to agricultural use of steroidalandrogens such as trenbolone acetate whose half-life is 3 days, is muchreduced, and comprises therefore an embodiment of an advantage of thecompounds of this invention.

In some embodiments, an advantage of the compounds/compositions of thisinvention may comprise the anabolic activity of the compound therebyproducing larger animals and affecting carcass composition in less time.Factors contributing to the increasing productivity may include, in someembodiments, enhanced mineral (and other nutrient) absorption in thegut; enhanced body protein accretion and metabolism of fat storesresulting in increased lean growth rates; increasing nitrogen uptake bymuscles, leading to an increase in the rate of protein synthesis andmuscle/bone growth.

In some embodiments, the present invention provides a method forenhanced production such as milk, sperm, or egg. In some embodiments,the present invention provides a method for enhanced production of leanmeats or eggs. In some embodiments, the present invention provides amethod for increased productivity of feeds or stud livestock, forexample, increased sperm count, improved morphology of sperm, etc. Insome embodiments, the present invention provides a method for expandingthe productive life of farm animals, for example, egg-laying hens,milk-producing cows, etc, and/or enhanced herd health, for example,improved immune clearance, stronger animals.

In one embodiment, this invention is directed to a method of affectingthe carcass composition of an animal comprising administering a compoundof this invention. In one embodiment, this invention is directed to amethod of affecting the carcass composition of an animal comprisingadministering a compound of formula IIIA or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof. In one embodiment, this invention is directedto a method of affecting the carcass composition of an animal comprisingadministering a to compound of formula I or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof. In one embodiment, this invention is directedto a method of affecting the carcass composition of an animal comprisingadministering a compound of formula II or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof. In one embodiment, this invention is directedto a method of affecting the carcass composition of an animal comprisingadministering a compound of formula XXIII its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof. In one embodiment, this invention is directedto a method of affecting the carcass composition of an animal comprisingadministering a compound of formula XXIV or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof. In one embodiment, this invention is directedto a method of affecting the carcass composition of an animal comprisingadministering a compound of formula XXV or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof. In another embodiment, the carcass compositionis affected by increasing the lean mass, reducing the fat mass, orreducing percent fat mass. In another embodiment, the carcasscomposition comprises increasing the growth performance in said animal.

In one embodiment, this invention is directed to a method of increasinglean mass of an animal comprising administering a compound of thisinvention. In one embodiment, this invention is directed to a method ofincreasing lean mass of an animal comprising administering a compound offormula IIIA or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof. In one embodiment, this invention is directed to a method ofincreasing lean mass of an animal comprising administering a compound offormula I or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof. In one embodiment, this invention is directed to a method ofincreasing lean mass of an animal comprising administering a compound offormula II or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof. In one embodiment, this invention is directed to a method ofincreasing lean mass of an animal comprising administering a compound offormula XXIII its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof. In one embodiment, this invention is directed to a method ofincreasing lean mass of an animal comprising administering a compound ofto formula XXIV or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof. In one embodiment, this invention is directed to a method ofincreasing lean mass of an animal comprising administering a compound offormula XXV or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof.

In one embodiment, this invention is directed to a method of reducingfat mass of an animal comprising administering a compound of thisinvention. In one embodiment, this invention is directed to a method ofreducing fat mass of an animal comprising administering a compound offormula IIIA or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof. In one embodiment, this invention is directed to a method ofreducing fat mass of an animal comprising administering a compound offormula I or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof. In one embodiment, this invention is directed to a method ofreducing fat mass of an animal comprising administering a compound offormula II or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof. In one embodiment, this invention is directed to a method ofreducing fat mass of an animal comprising administering a compound offormula XXIII its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof. In one embodiment, this invention is directed to a method ofreducing fat mass of an animal comprising administering a compound offormula XXIV or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof. In one embodiment, this invention is directed to a method ofreducing fat mass of an animal comprising administering a compound offormula XXV or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof.

In one embodiment, this invention is directed to a method of reducingpercent fat mass of an animal comprising administering a compound ofthis invention. In one embodiment, this invention is directed to amethod of reducing percent fat mass of an animal comprisingadministering a compound of formula IIIA or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof. In one embodiment, this invention is directedto a method of reducing percent fat mass of an animal comprisingadministering a compound of formula I or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof. In one embodiment, this invention is directedto a method of reducing to percent fat mass of an animal comprisingadministering a compound of formula II or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof. In one embodiment, this invention is directedto a method of reducing percent fat mass of an animal comprisingadministering a compound of formula XXIII its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, is hydrate orany combination thereof. In one embodiment, this invention is directedto a method of reducing percent fat mass of an animal comprisingadministering a compound of formula XXIV or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof. In one embodiment, this invention is directedto a method of reducing percent fat mass of an animal comprisingadministering a compound of formula XXV or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof.

In one embodiment, this invention is directed to a method of increasingfeed efficiency of an animal comprising administering a compound of thisinvention. In one embodiment, this invention is directed to a method ofincreasing feed efficiency of an animal comprising administering acompound of formula IIIA or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, crystal, N-oxide, hydrate or anycombination thereof. In one embodiment, this invention is directed to amethod of increasing feed efficiency of an animal comprisingadministering a compound of formula I or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof. In one embodiment, this invention is directedto a method of increasing feed efficiency of an animal comprisingadministering a compound of formula II or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof. In one embodiment, this invention is directedto a method of increasing feed efficiency of an animal comprisingadministering a compound of formula XXIII its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof. In one embodiment, this invention is directedto a method of increasing feed efficiency of an animal comprisingadministering a compound of formula XXIV or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof. In one embodiment, this invention is directedto a method of increasing feed efficiency of an animal comprisingadministering a compound of formula XXV or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof.

In one embodiment, this invention is directed to a method of increasingaverage to daily gain (ADG) of an animal comprising administering acompound of this invention. In one embodiment, this invention isdirected to a method of increasing average daily gain (ADG) of an animalcomprising administering a compound of formula IIIA or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,N-oxide, hydrate or any combination thereof. In one embodiment, thisinvention is directed to a method of is increasing average daily gain(ADG) of an animal comprising administering a compound of formula I orits isomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof. In one embodiment,this invention is directed to a method of increasing average daily gain(ADG) of an animal comprising administering a compound of formula II orits isomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof. In one embodiment,this invention is directed to a method of increasing average daily gain(ADG) of an animal comprising administering a compound of formula XXIIIits isomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof. In one embodiment,this invention is directed to a method of increasing average daily gain(ADG) of an animal comprising administering a compound of formula XXIVor its isomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof. In one embodiment,this invention is directed to a method of increasing average daily gain(ADG) of an animal comprising administering a compound of formula XXV orits isomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof.

In one embodiment, this invention is directed to a method of decreasingfeed to gain ratio (F:G) of an animal comprising administering acompound of this invention. In one embodiment, this invention isdirected to a method of decreasing feed to gain ratio (F:G) of an animalcomprising administering a compound of formula IIIA or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,N-oxide, hydrate or any combination thereof. In one embodiment, thisinvention is directed to a method of decreasing feed to gain ratio (F:G)of an animal comprising administering a compound of formula I or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof. In one embodiment,this invention is directed to a method of decreasing feed to gain ratio(F:G) of an animal comprising administering a compound of formula II orits isomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof. In one embodiment,this invention is directed to a method of decreasing feed to gain ratio(F:G) of an animal comprising administering a compound of formula XXIIIits isomer, pharmaceutically to acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof. In one embodiment,this invention is directed to a method of decreasing feed to gain ratio(F:G) of an animal comprising administering a compound of formula XXIVor its isomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof. In one embodiment,this invention is directed to a method of decreasing feed to gain ratio(F:G) of an animal comprising administering a compound of formula XXV orits isomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof.

In one embodiment the compounds, compositions and methods of thisinvention decrease the fat mass of an animal by 2-15%. In anotherembodiment, decrease the fat mass of an animal by 2-10%. In anotherembodiment, decrease the fat mass of an animal by 5-10%. In anotherembodiment, decrease the fat mass of an animal by 5-15%. In anotherembodiment, the animal is a pig. In another embodiment the animal is abeef cattle. In another embodiment, the animal is a finishing livestock.In another embodiment the animal is a feedlot animal.

In another embodiment the methods and/or compositions of this inventionmake use of the compounds of this invention for decreasing the fat massof an animal by 5-15% after 7-28 days. In another embodiment the methodsand/or compositions of this invention make use of the compounds of thisinvention for decreasing the fat mass of an animal by 5-15% after 7-14days. In another embodiment the methods and/or compositions of thisinvention make use of the compounds of this invention for decreasing thefat mass of an animal by 5-15% after 14-21 days. In another embodimentthe methods and/or compositions of this invention make use of thecompounds of this invention for decreasing the fat mass of an animal by5-15% after 21-28 days. In another embodiment the methods and/orcompositions of this invention make use of the compounds of thisinvention for decreasing the fat mass of an animal by 5-15% after 28-60days.

In one embodiment the compounds, compositions and methods of thisinvention increase lean mass of an animal by 5-15%. In anotherembodiment, increase lean mass of an animal by 5-10%. In anotherembodiment, increase lean mass of an animal by 8-10%. In anotherembodiment, increase lean mass of an animal by 15-30%. In anotherembodiment, the animal is a pig. In another embodiment the animal isbeef cattle. In another embodiment, the animal is a finishing livestock.In another embodiment the animal is a feedlot animal.

In another embodiment the methods and/or compositions of this inventionmake use of the compounds of this invention for increasing lean mass ofan animal by 5-15% after 7-28 days. In another embodiment the methodsand/or compositions of this invention make use of the compounds of thisinvention for increasing lean mass of an animal by 5-15% after 7-14days. In another embodiment the methods and/or compositions of thisinvention make use of the compounds of this invention for increasinglean mass of an animal by 5-15% after 14-21 days. In another embodimentthe methods and/or is compositions of this invention make use of thecompounds of this invention for increasing lean mass of an animal by5-15% after 21-28 days. In another embodiment the methods and/orcompositions of this invention make use of the compounds of thisinvention for increasing lean mass of an animal by 5-15% after 28-60days. In another embodiment the methods and/or compositions of thisinvention make use of the compounds of this invention for increasinglean mass of an animal by 15-30% after 7-28 days. In another embodimentthe methods and/or compositions of this invention make use of thecompounds of this invention for increasing lean mass of an animal by15-30% after 7-14 days. In another embodiment the methods and/orcompositions of this invention make use of the compounds of thisinvention for increasing lean mass of an animal by 15-30% after 14-21days. In another embodiment the methods and/or compositions of thisinvention make use of the compounds of this invention for increasinglean mass of an animal by 15-30% after 21-28 days. In another embodimentthe methods and/or compositions of this invention make use of thecompounds of this invention for increasing lean mass of an animal by15-30% after 28-60 days.

In one embodiment, the methods of this invention include administering acompound and/or feeding composition to an animal. In another embodiment,the compound and/or feed composition is provided in the daily feed tothe animal. In another embodiment, the feed composition comprises acompound of this invention. In another embodiment, the feed compositioncomprises a combination of a compound of this invention and abeta-agonist. In another embodiment, the beta-agonist is Ractopaminehydrochloride (Paylean®).

The pharmaceutical compositions and feed composition containing thecompounds of this invention can be administered to a subject by anymethod known to a person skilled in the art, such as orally,parenterally, intravascularly, paracancerally, transmucosally,transdermally, intramuscularly, intranasally, intravenously,intradermally, subcutaneously, sublingually, intraperitoneally,intraventricularly, intracranially, intravaginally, by inhalation,rectally, intratumorally, or by any means in which the recombinantvirus/composition can be delivered to tissue (e.g., needle or catheter).Alternatively, topical administration may be desired for application tomucosal cells, for skin or ocular application. Another method ofadministration is via aspiration or aerosol formulation.

In one embodiment, the pharmaceutical compositions are administeredorally, and are thus formulated in a form suitable for oraladministration, i.e. as a solid or a liquid preparation. Suitable solidoral formulations include tablets, capsules, pills, granules, pellets,powders, and the like. Suitable liquid oral formulations includesolutions, suspensions, dispersions, emulsions, oils and the like. Inone embodiment of the present invention, the SARM compounds areformulated in a capsule. In accordance with this embodiment, thecompositions of the present invention comprise in addition to a compoundof this invention and the inert carrier or diluent, a hard gelatincapsule.

In one embodiment, the micronized capsules comprise particles containinga compound of this invention, wherein the term “micronized” used hereinrefers to particles having a particle size is of less than 100 microns,or in another embodiment, less than 60 microns, or in anotherembodiment, less than 36 microns, or in another embodiment, less than 16microns, or in another embodiment, less than 10 microns, or in anotherembodiment, less than 6 microns.

Further, in another embodiment, the pharmaceutical compositions areadministered by intravenous, intraarterial, or intramuscular injectionof a liquid preparation. Suitable liquid formulations include solutions,suspensions, dispersions, emulsions, oils and the like. In oneembodiment, the pharmaceutical compositions are administeredintravenously, and are thus formulated in a form suitable forintravenous administration. In another embodiment, the pharmaceuticalcompositions are administered intraarterially, and are thus formulatedin a form suitable for intraarterial administration. In anotherembodiment, the pharmaceutical compositions are administeredintramuscularly, and are thus formulated in a form suitable forintramuscular administration.

Further, in another embodiment, the pharmaceutical compositions areadministered topically to body surfaces, and are thus formulated in aform suitable for topical administration. Suitable topical formulationsinclude gels, ointments, creams, lotions, drops and the like. Fortopical administration, the compounds of this invention or theirphysiologically tolerated derivatives such as salts, esters, N-oxides,and the like are prepared and applied as solutions, suspensions, oremulsions in a physiologically acceptable diluent with or without apharmaceutical carrier.

Further, in another embodiment, the pharmaceutical compositions are toadministered as a suppository, for example a rectal suppository or aurethral suppository. Further, in another embodiment, the pharmaceuticalcompositions are administered by subcutaneous implantation of a pellet.In a further embodiment, the pellet provides for controlled release of acompound as herein described over a period of time. In a furtherembodiment, the pharmaceutical compositions are administeredintravaginally.

In another embodiment, the active compound can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1627-1633(1990); Treat et al., in Liposomes in the Therapy of Infectious Diseaseand Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp.363-366 (1989); Lopez-Berestein, ibid., pp. 317-327; see generallyibid).

As used herein “pharmaceutically acceptable carriers or diluents” arewell known to those skilled in the art. The carrier or diluent may be asolid carrier or diluent for solid formulations, a liquid carrier ordiluent for liquid formulations, or mixtures thereof.

Solid carriers/diluents include, but are not limited to, a gum, a starch(e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose,mannitol, sucrose, dextrose), a cellulosic material (e.g.microcrystalline cellulose), an acrylate (e.g. polymethylacrylate),calcium carbonate, magnesium oxide, talc, or mixtures thereof.

In one embodiment, the compositions of this invention may include, acompound of this invention or any combination thereof, together with oneor more pharmaceutically acceptable excipients.

It is to be understood that this invention encompasses any embodiment ofa compound as described herein, which in some embodiments is referred toas “a compound of this invention”. Such reference will include anycompound, which is characterized by a structure of the formulas I-XXV,or any embodiment thereof, as described herein.

Suitable excipients and carriers may be, according to embodiments of theinvention, solid or liquid and the type is generally chosen based on thetype of administration being used. Liposomes may also be used to deliverthe composition. Examples of suitable solid carriers include lactose,sucrose, gelatin and agar. Oral dosage forms may contain suitablebinders, lubricants, diluents, disintegrating agents, coloring agents,flavoring agents, flow-inducing agents, and melting agents. Liquiddosage forms may contain, for example, suitable solvents, preservatives,emulsifying agents, suspending agents, diluents, sweeteners, thickeners,and melting agents. Parenteral and intravenous forms should also includeminerals and other materials to make them compatible with the type ofinjection or delivery system chosen. Of course, to other excipients mayalso be used.

For liquid formulations, pharmaceutically acceptable carriers may beaqueous or non-aqueous solutions, suspensions, emulsions or oils.Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, and injectable organic esters such as ethyl oleate. Aqueouscarriers include water, alcoholic/aqueous solutions, cyclodextrins,emulsions or suspensions, including saline and buffered media. Examplesof oils are those of petroleum, animal, vegetable, or synthetic origin,for example, peanut oil, soybean oil, mineral oil, olive oil, sunfloweroil, and fish-liver oil.

Parenteral vehicles (for subcutaneous, intravenous, intraarterial, orintramuscular injection) include sodium chloride solution, Ringersdextrose, dextrose and sodium chloride, lactated Ringer's and fixedoils. Intravenous vehicles include fluid and nutrient replenishers,electrolyte replenishers such as those based on Ringer's dextrose, andthe like. Examples are sterile liquids such as water and oils, with orwithout the addition of a surfactant and other pharmaceuticallyacceptable adjuvants. In general, water, saline, aqueous dextrose andrelated sugar solutions, and glycols such as propylene glycols orpolyethylene glycol are preferred liquid carriers, particularly forinjectable solutions. Examples of oils are those of petroleum, animal,vegetable, or synthetic origin, for example, peanut oil, soybean oil,mineral oil, olive oil, sunflower oil, and fish-liver oil.

In addition, the compositions may further comprise binders (e.g. acacia,cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropylcellulose, hydroxypropyl methyl cellulose, povidone), disintegratingagents (e.g. cornstarch, potato starch, alginic acid, silicon dioxide,croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate),buffers (e.g., Tris-HCl, acetate, phosphate) of various pH and ionicstrength, additives such as albumin or gelatin to prevent absorption tosurfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acidsalts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate),permeation enhancers, solubilizing agents (e.g., cremophor, glycerol,polyethylene glycerol, benzlkonium chloride, benzyl benzoate,cyclodextrins, sobitan esters, stearic acids), anti-oxidants (e.g.,ascorbic acid, sodium metabisulfite, butylated hydroxyanisole),stabilizers (e.g. hydroxypropyl cellulose, hyroxypropylmethylcellulose), viscosity increasing agents (e.g. carbomer, colloidalsilicon dioxide, ethyl cellulose, guar gum), sweetners (e.g. aspartame,citric acid), preservatives (e.g., Thimerosal, benzyl alcohol,parabens), coloring agents, lubricants (e.g. stearic acid, magnesiumstearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g.colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate,triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose,sodium lauryl sulfate), polymer coatings (e.g., poloxamers orpoloxamines), coating and film forming agents (e.g. ethyl cellulose,acrylates, polymethacrylates), and/or adjuvants.

In one embodiment, the pharmaceutical compositions provided herein arecontrolled release compositions, i.e. compositions in which the compoundof this is invention is released over a period of time afteradministration. Controlled or sustained release compositions includeformulation in lipophilic depots (e.g. fatty acids, waxes, oils).

In another embodiment, the composition is an immediate releasecomposition, i.e. a composition in which all of the compound is releasedimmediately after administration.

In yet another embodiment, the pharmaceutical composition can bedelivered in a controlled release system. For example, the agent may beadministered using intravenous infusion, an implantable osmotic pump, atransdermal patch, liposomes, or other modes of administration. In oneembodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit.Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:607 (1980);Saudek et al., N. Engl. J. Med. 321:674 (1989). In another embodiment,polymeric materials can be used. In yet another embodiment, a controlledrelease system can be placed in proximity to the therapeutic target,i.e., the brain, thus requiring only a fraction of the systemic dose(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 116-138 (1984). Other controlled release systems arediscussed in the review by Langer (Science 249:1627-1633 (1990).

The compositions may also include incorporation of the active materialinto or onto particulate preparations of polymeric compounds such aspolylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes,microemulsions, micelles, unilamellar or multilamellar vesicles,erythrocyte ghosts, or spheroplasts.) Such compositions will influencethe physical state, solubility, stability, rate of in vivo release, andrate of in vivo clearance.

Also comprehended by the invention are particulate compositions coatedwith polymers (e.g. poloxamers or poloxamines) and the compound coupledto antibodies directed against tissue-specific receptors, ligands orantigens or coupled to ligands of tissue-specific receptors.

Also comprehended by the invention are compounds modified by thecovalent attachment of water-soluble polymers such as polyethyleneglycol, copolymers of polyethylene glycol and polypropylene glycol,carboxymethyl cellulose, dextran, polyvinyl alcohol,polyvinylpyrrolidone or polyproline. The modified compounds are known toexhibit substantially longer half-lives in blood following intravenousinjection than do the corresponding unmodified compounds (Abuchowski etal., 1981; Newmark et al., 1982; and Katre et al., 1987). Suchmodifications may also increase the compound's solubility in aqueoussolution, eliminate aggregation, enhance the physical and chemicalstability of the compound, and greatly reduce the immunogenicity andreactivity of the compound. As a result, the desired in vivo biologicalactivity may be achieved by the is administration of suchpolymer-compound abducts less frequently or in lower doses than with theunmodified compound.

The preparation of pharmaceutical compositions which contain an activecomponent is well understood in the art, for example by mixing,granulating, or tablet-forming processes. The active therapeuticingredient is often mixed with excipients which are pharmaceuticallyacceptable and compatible with the active ingredient. For oraladministration, the compounds of this invention or their physiologicallytolerated derivatives such as salts, esters, N-oxides, and the like aremixed with additives customary for this purpose, such as vehicles,stabilizers, or inert diluents, and converted by customary methods intosuitable forms for administration, such as tablets, coated tablets, hardor soft gelatin capsules, aqueous, alcoholic or oily solutions. Forparenteral administration, the compounds of this invention or theirphysiologically tolerated derivatives such as salts, esters, N-oxides,and the like are converted into a solution, suspension, or emulsion, ifdesired with the substances customary and suitable for this purpose, forexample, solubilizers or other.

An active component can be formulated into the composition asneutralized pharmaceutically acceptable salt forms. Pharmaceuticallyacceptable salts include the acid addition salts (formed with the freeamino groups of the polypeptide or antibody molecule), which are formedwith inorganic acids such as, for example, hydrochloric or phosphoricacids, or such organic acids as acetic, oxalic, tartaric, mandelic, andthe like. Salts formed from the free carboxyl groups can also be derivedfrom inorganic bases such as, for example, sodium, potassium, ammonium,calcium, or ferric hydroxides, and such organic bases as isopropylamine,trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.

For use in medicine, the salts of the compound will be pharmaceuticallyacceptable salts. Other salts may, however, be useful in the preparationof the compounds according to the invention or of their pharmaceuticallyacceptable salts. Suitable pharmaceutically acceptable salts of thecompounds of this invention include acid addition salts which may, forexample, be formed by mixing a solution of the compound according to theinvention with a solution of a pharmaceutically acceptable to acid suchas hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaricacid, maleic acid, succinic acid, acetic acid, benzoic: acid, oxalicacid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

In one embodiment, this invention provides pharmaceutical compositionscomprising a compound of this invention. In one embodiment, suchcompositions are is useful for oral testosterone replacement therapy.

In one embodiment, this invention also provides a composition comprisingtwo or more compounds of this invention, or polymorphs, isomers,hydrates, salts, N-oxides, etc., thereof. The present invention alsorelates to compositions and pharmaceutical compositions which comprise acompound of this invention alone or in combination with a progestin orestrogen, or in another embodiment, chemotherapeutic compound,osteogenic or myogenic compound, or other agents suitable for theapplications as herein described. In one embodiment, the compositions ofthis invention will comprise a suitable carrier, diluent or salt.

In one embodiment, the methods of this invention may compriseadministration of a compound of this invention at various dosages. Inanother embodiment, the methods of this invention may compriseadministration of a compound of formula II of this invention at variousdosages. In one embodiment, the compound of this invention isadministered at a dosage of 0.1-200 mg per day. In one embodiment, thecompound of this invention is administered at a dose of 0.1-10 mg, or inanother embodiment, 0.1-26 mg, or in another embodiment, 0.1-60 mg, orin another embodiment, 0.3-16 mg, or in another embodiment, 0.3-30 mg,or in another embodiment, 0.6-26 mg, or in another embodiment, 0.6-60mg, or in another embodiment, 0.76-16 mg, or in another embodiment,0.76-60 mg, or in another embodiment, 1-6 mg, or in another embodiment,1-20 mg, or in another embodiment, 3-16 mg, or in another embodiment,30-60 mg, or in another embodiment, 30-76 mg, or in another embodiment,100-2000 mg, or in another embodiment, 1000-20,000 mg.

In one embodiment, the methods of this invention may compriseadministration of a compound of this invention at various dosages. Inanother embodiment, the methods of this invention may compriseadministration of a compound of formula II of this invention at variousdosages. In one embodiment, the compound of this invention isadministered at a dosage of 1 mg. In another embodiment the compound ofthis invention is administered at a dosage of 6 mg, 10 mg, 16 mg, 20 mg,26 mg, 30 mg, 36 mg, 40 mg, 46 mg, 50 mg, 56 mg, 60 mg, 66 mg, 70 mg, 76mg, 80 mg, 86 mg, to 90 mg, 96 mg, 100 mg, 200 mg, 500 mg, 1000 mg, 2000mg, 10,000 mg, or 20,000 mg.

In one embodiment, the present invention provides methods of usecomprising the administration of a composition comprising a) anyembodiment of a compound as described herein; and b) additives, apharmaceutically acceptable carrier or diluent; which is to beunderstood to include an analog, isomer, metabolite, derivative, ispharmaceutically acceptable salt, N-oxide, hydrate or any combinationthereof of a compound as herein described, and may comprise compounds offormulas I-XXV.

In some embodiments, the present invention provides methods of use of acomposition comprising a) any embodiment of the compounds as describedherein, including an analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, N-oxide,hydrate thereof or any combination thereof; b) a pharmaceuticallyacceptable carrier or diluent; c) a flow-aid; and d) a lubricant.

In another embodiment, the present invention provides methods of use ofa composition comprising a) any embodiment of the compounds as describedherein, including an analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, N-oxide,hydrate thereof or any combination thereof; b) lactose monohydrate; c)microcrystalline cellulose; d) magnesium stearate; e) additives and f)colloidal silicon dioxide.

In some embodiments, the methods of this invention make use ofcompositions comprising compounds of this invention, which offer theadvantage that the compounds are nonsteroidal ligands for the androgenreceptor, and exhibit anabolic activity in vivo. According to thisaspect, such compounds are unaccompanied by serious side effects,provide convenient modes of administration, and lower production costsand are orally bioavailable, lack of significant cross-reactivity withother undesired steroid receptors, and may possess long biologicalhalf-lives.

In one embodiment, the compositions for administration may be sterilesolutions, or in other embodiments, aqueous or non-aqueous, suspensionsor emulsions. In one embodiment, the compositions may comprise propyleneglycol, polyethylene glycol, injectable organic esters, for exampleethyl oleate, or cyclodextrins. In another embodiment, compositions mayalso comprise wetting, emulsifying and/or dispersing agents. In anotherembodiment, the compositions may also comprise sterile water or anyother sterile injectable medium.

In one embodiment, the invention provides compounds and compositions,including any embodiment described herein, for use in any of the methodsof this invention, as described herein. In one embodiment, use of acompound of this invention or a composition comprising the same, willhave utility in inhibiting, suppressing, enhancing or stimulating adesired response in a subject, as will be understood by one skilled inthe art. In another embodiment, the compositions may further compriseadditional active ingredients, whose activity is useful for theparticular application for which the compound of this invention is beingadministered.

In some embodiments, the methods of this invention make use ofcompositions comprising compounds of this invention, which offer theadvantage that the compounds are nonsteroidal ligands for the androgenreceptor, and exhibit anabolic activity in vivo. According to thisaspect, such compounds are unaccompanied by serious side effects,provide convenient modes of administration, and lower production costsand are orally bioavailable, lack significant cross-reactivity withother undesired steroid receptors, and may possess long biologicalhalf-lives.

In some embodiments, the compositions will further comprise a5α-reductase inhibitors (5AR1), a beta-agonist, a SARM or SARMs, aselective estrogen receptor modulator (SERM), an aromatase inhibitor,such as but not limited to anastrazole, exemestane, or letrozole; a GnRHagonist or antagonist, a steroidal or nonsteroidal GR ligand, asteroidal or nonsterodial PR ligand, a steroidal or nonsteroidal ARantagonist, a 17-aldoketoreductase inhibitor or 17β-hydroxysteroiddehydrogenase inhibitor. Such compositions may be used, in someembodiments, for treating a hormone dependent condition, such as, forexample, infertility, neoplasia of a hormone-responsive cancer, forexample, a gonadal cancer, or a urogenital cancer.

In some embodiments, the composition will comprise the compounds asdescribed herein, as well as another therapeutic compound, includinginter alia, a 5AR1 such as finasteride, dutasteride, izonsteride; otherSARMs, such as, RU-58642, RU-56279, WS9761 A and B, RU-59063, RU-58841,bexlosteride, LG-2293, L-245976, LG-121071, LG-121091, LG-121104,LGD-2226, LGD-2941, YM-92088, YM-175735, LGD-1331, BMS-357597,BMS-391197, S-40503, BMS-482404, EM-4283, EM-4977, BMS-564929,BMS-391197, BMS-434588, BMS-487745, BMS-501949, SA-766, YM-92088,YM-580, LG-123303, LG-123129, PMCoI, YM-175735, BMS-591305, BMS-591309,BMS-665139, BMS-665539, CE-590, 116BG33, 154BG31, arcarine, ACP-105;SERMs, such as tamoxifene, 4-hydroxytamoxifene, idoxifene, toremifene,ospemifene, droloxifene, raloxifene, arzoxifene, bazedoxifene, PPT(1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole), DPN, lasofoxifene,pipendoxifene, EM-800, EM-652, nafoxidine, zindoxifene, tesmilifene,miproxifene phosphate, RU 58,688, EM 139, ICI-164,384, ICI-182,780,clomiphene, MER-25, diethylstibestrol, coumestrol, genistein, GW5638,LY353581, zuclomiphene, enclomiphene, delmadinone acetate, DPPE,(N,N-diethyl-2-{4-(phenylmethyl)-phenoxy}ethanamine), TSE-424, WAY-070,WAY-292, WAY-818, cyclocommunol, prinaberel, ERB-041, WAY-397, WAY-244,ERB-196, WAY-169122, MF-101, ERb-002, ERB-037, ERB-017, BE-1060, BE-380,BE-381, WAY-358, [¹⁸F]FEDNP, LSN-500307, AA-102, Ban zhi lian, CT-101,CT-102, VG-101; GnRH agonists or antagonists, such as, leuprolide,goserelin, triptorelin, alfaprostol, histrelin, detirelix, ganirelix,antide iturelix, cetrorelix, ramorelix, ganirelix, antarelix, teverelix,abarelix, ozarelix, sufugolix, prazarelix, degarelix, NBI-56418,TAK-810, acyline; FSH agonist/antagonist, LH agonist/antagonists,aromatase inhibitors, such as, letrozole, anastrazole, atamestane,fadrozole, minamestane, exemestane, plomestane, liarozole, NKS-01,vorozole, YM-511, finrozole, 4-hydroxyandrostenedione, aminogluethimide,rogletimide; Steroidal or nonsteroidal glucocorticoid receptor ligands,such as, ZK-216348, ZK-243149, ZK-243185, LGD-5552, mifepristone,RPR-106541, ORG-34517, GW-215864X, Sesquicillin, CP-472555, CP-394531,A-222977, AL-438, A-216054, A-276575, CP-394531, CP-409069, UGR-07;Steroidal or nonsterodial progesterone receptor ligands; Steroidal ornonsteroidal AR antagonists such as flutamide, hydroxyflutamide,bicalutamide, nilutamide, hydroxysteroid dehydrogenase inhibitors, PPARαligand such as bezafibrate, fenofibrate, gemfibrozil; PPAR ligands suchas darglitazone, pioglitazone, rosiglitazone, isaglitazone,rivoglitazone, netoglitazone; Dual acting PPAR ligands, such asnaveglitazar, farglitazar, tesaglitazar, ragaglitazar, oxeglitazar,PN-2034, PPAR δ; an anti-glucocorticoid such as RU-486; a17-ketoreductase inhibitors, 3β-ΔHΔ4,6-isomerase inhibitors,3β-ΔHΔ4,5-isomerase inhibitors, 17,20-desmolase inhibitors, p450c17inhibitors, p450ssc inhibitors, 17,20-lyase inhibitors, or combinationsthereof.

In some embodiments, the compositions will further comprise Ghrelinreceptor ligand or growth hormone analogues and secretagogues, IGF-1,IGF-1 analogues and secretagogues, myostatin analogues, proteasomeinhibitors, androgenic-anabolic steroids, Enbrel, melanocortin 4receptor agonist, insulins, or combinations thereof. Such compositionsmay be used, in some embodiments, for promoting growth in feedlotanimals.

In some embodiments, the composition will comprise the compounds asdescribed herein, as well as another therapeutic compound, includinginter alia, ghrelin receptor ligand or growth hormone analogues andsecretagogues, such as, pralmorelin, examorelin, tabimorelin,capimorelin, capromorelin, ipamorelin, EP-01572, EP-1572, JMV-1843, anandrogenic anabolic steroid such as testosterone or oxandrolone; amelanocortin 4 receptor agonist, such as bremelanotide, a ghrelin oranalogue thereof, such as human ghrelin, CYT-009-GhrQb, L-692429,GHRP-6, SK&F-110679, U-75799E), leptin (metreleptin, pegylated leptin; aleptin receptor agonist, such as LEP(116-130), OB3, [D-Leu4]-OB3,rAAV-leptin, AAV-hOB, rAAVhOB; an insulin (short-, intermediate-, andlong acting formulations); a cortisol or corticosteroid, or acombination thereof.

The invention contemplates, in some embodiments, administration ofcompositions comprising the individual agents, administered separatelyand by similar or alternative routes, formulated as appropriately forthe route of administration. The invention contemplates, in someembodiments, administration of compositions comprising the individualagents, administered in the same formulation. The inventioncontemplates, in some embodiments, staggered administration, concurrentadministration, of administration of the various agents over a course oftime, however, their effects are synergistic in the subject.

It is to be understood that any of the above means, timings, routes, orcombinations thereof, of administration of two or more agents is to beconsidered as being encompassed by the phrase “administered incombination”, as described herein.

It is to be understood that reference to “a compound of this invention”or a use thereof is to be considered to encompass use of any compound asherein described, including any embodiment thereof. It is to beconsidered to encompass all of compounds which may be characterized bythe structure of formulas I-XXV.

In one embodiment, the compound is administered in combination with anagent, which treats bone diseases, disorders or conditions, such asosteoporosis, bone fractures, etc., and this invention comprises methodsof treating the same, by administering the compounds as hereindescribed, alone or in combination with other agents.

Such agents for combined use may comprise a SERM, as herein described, abisphosphonate, for example, alendronate, tiludroate, clodroniate,pamidronate, etidronate, alendronate, zolendronate, cimadronate,neridronate, minodronic acid, ibandronate, risedronate, homoresidronate,a calcitonin, for example, salmon, Elcatonin, SUN-8577, TJN-135; aVitamin D or derivative (ZK-156979); a Vitamin D receptor ligand oranalogues thereof, such as calcitriol, topitriol, ZK-150123, TEI-9647,BXL-628, Ro-26-9228, BAL-2299, Ro-65-2299, DP-035, an estrogen, estrogenderivative, or conjugated estrogen; an antiestrogen, progestin,synthetic estrogen/progestin; a RANK ligand mAb, for example, denosumabor AMG162 (Amgen); a beta 3 integrin receptor antagonist; an osteoclastvacuolar ATPase inhibitor; an antagonist of VEGF binding to osteoclastreceptors; a calcium receptor antagonist; PTh (parathyroid hormone) oranalogues thereof, PTHrP analogues (parathyroid hormone-relatedpeptide), Cathepsin K inhibitors (AAE581); Strontium ranelate; Tibolone;HCT-1026, PSK3471; Gallium maltolate; Nutropin AQ; Prostaglandins, p38protein kinase inhibitor; a bone morphogenetic protein; an inhibitor ofBMP antagonism, an. HMG-CoA reductase inhibitor, a Vitamin K orderivative, an antiresorptive, an Ipriflavone, a fluoride salt, dietarycalcium supplement, Osteoprotegerin, or any combination thereof. In oneembodiment, the combined administration of a SARM as herein described,Osteoprotegerin and parathyroid hormone is contemplated for treating anydisease, disorder or condition of the bone.

In one embodiment, the compound is administered with an agent used totreat a wasting disease. In some embodiments, agents used to treat awasting disease include but are not limited to corticosteroids, anabolicsteroids, cannabinoids, metoclopramide, cisapride, medroxyprogesteroneacetate, megestrol acetate, cyproheptadine, hydrazine sulfate,pentoxifylline, thalidomide, anticytokine antibodies, cytokineinhibitors, eicosapentaenoic acid, indomethacin, ibuprofen, melatonin,insulin, growth hormone, clenbuterol, porcine pancreas extract, IGF-1,IGF-1 analogue and secretagogue, myostatin analogue, proteasomeinhibitor, testosterone, oxandrolone, Enbrel, melanocortin 4 receptoragonist, or a combination thereof.

In one embodiment, the agent used to treat a wasting disease is aghrelin receptor ligand, growth hormone analogue, or a secretagogue. Insome embodiments, ghrelin receptor ligands, growth hormone analogues, orsecretagogues include but are not limited to pralmorelin, examorelin,tabimorelin, capimorelin, capromorelin, ipamorelin, EP-01572, EP-1572,or JMV-1843.

In one embodiment, growth promoting agents such as but not limited toTRH, diethylstilbesterol, theophylline, enkephalins, E seriesprostaglandins, compounds disclosed in U.S. Pat. No. 3,239,345, e.g.,zeranol, and compounds disclosed in U.S. Pat. No. 4,036,979, e.g.,sulbenox or peptides disclosed in U.S. Pat. No. 4,411,890 are utilizedas agents used to treat a wasting disease.

In other embodiments, agents treating a wasting disease may comprisegrowth hormone secretagogues such as GHRP-6, GHRP-1 (as described inU.S. Pat. No. 4,411,890 and publications WO 89/07110 and WO 89/07111),GHRP-2 (as described in WO 93/04081), NN₇O₃ (Novo Nordisk), LY444711(Lilly), MK-677 (Merck), CP424391 (Pfizer) and B-HT920, or, in otherembodiments, with growth hormone releasing factor and its analogs orgrowth hormone and its analogs, or with alpha-adrenergic agonists, suchas clonidine or serotinin 5-HTD agonists, such as sumatriptan, or agentswhich is inhibit somatostatin or its release, such as physostigmine andpyridostigmine. In some embodiments, agents treating a wasting diseasemay comprise parathyroid hormone, PTH (1-34) or bisphosphonates, such asMK-217 (alendronate). In other embodiments, agents treating wastingdisease may further comprise estrogen, a selective estrogen receptormodulator, such as tamoxifene or raloxifene, or other androgen receptormodulators, such as those disclosed in Edwards, J. P. et. al., Bio. Med.Chem. Let., 9, 1003-1008 (1999) and Hamann, L. G. et. al., J. Med.Chem., 42, 210-212 (1999). In some embodiments, agents treating awasting disease may further comprise a progesterone receptor agonists(“PRA”), such as levonorgestrel, medroxyprogesterone acetate (MPA). Insome embodiments, agents treating a wasting disease may includenutritional supplements, such as those described in U.S. Pat. No.5,179,080, which, in other embodiments are in combination with wheyprotein or casein, amino acids (such as leucine, branched amino acidsand hydroxymethylbutyrate), triglycerides, vitamins (e.g., A, B6, B 12,folate, C, D and E), minerals (e.g., selenium, magnesium, zinc,chromium, calcium and potassium), camitine, lipoic acid, creatinine,B-hyroxy-B-methylbutyriate (Juven) and coenzyme Q. In one embodiment,agents treating a wasting disease may further comprise antiresorptiveagents, vitamin D analogues, elemental calcium and calcium supplements,cathepsin K inhibitors, MMP inhibitors, vitronectin receptorantagonists, Src SH2 antagonists, vacular-H⁺-ATPase inhibitors,ipriflavone, fluoride, tibolone, prostanoids, 17-beta hydroxysteroiddehydrogenase inhibitors and Src kinase inhibitors.

In one embodiment, the SARM compound is administered with an agenttreating osteoporosis. In some embodiments, agents treating osteoporosisinclude but are not limited to SERMs, calcitonin, vitamin D, vitamin Dderivatives, vitamin D receptor ligand, vitamin D receptor ligandanalogue, estrogen, estrogen derivative, conjugated estrogen,antiestrogen, progestin, synthetic estrogen, synthetic progestin, RANKligand monoclonal antibody, integrin receptor antagonist, osteoclastvacuolar ATPase inhibitor, antagonist of VEGF binding to osteoclastreceptors, calcium receptor antagonist, parathyroid hormone, parathyroidhormone analogue, parathyroid hormone-related peptide, cathepsin Kinhibitor, strontium ranelate, tibolone, HCT-1026, PSK3471, galliummaltolate, nutropin AQ, prostaglandin, p38 protein kinase inhibitor,bone morphogenetic protein (BMP), inhibitor of BMP antagonism, HMG-CoAreductase inhibitor, vitamin K, vitamin K derivative, ipriflavone,fluoride salts, dietary calcium supplement, or osteoprotegerin.

In one embodiment, the agent treating osteoporosis is a calcitonin. Insome embodiments, calcitonins include but are not limited to salmon,elcatonin, SUN-8577, or TJN-135.

In one embodiment, the agent treating osteoporosis is a vitamin Dreceptor ligand or analogue. In some embodiments, vitamin D receptorligands or analogues include but are not limited to calcitriol,topitriol, ZK-150123, TEI-9647, BXL-628, Ro-26-9228, BAL-2299,Ro-65-2299, or DP-035.

In one embodiment, the compound of this invention is administered with avitamin. In some embodiments, vitamins include but are not limited tovitamin D, vitamin E, vitamin K, vitamin B, vitamin C, or a combinationthereof.

In some embodiments, any of the compositions of this invention willcomprise a compound of formula I-XXV, in any form or embodiment asdescribed herein. In some embodiments, any of the compositions of thisinvention will consist of a compound of formula I-XXV, in any form orembodiment as described herein. In some embodiments, of the compositionsof this invention will consist essentially of a compound of 1-XXV, inany form or embodiment as described herein. In some embodiments, theterm “comprise” refers to the inclusion of the indicated active agent,such as the compound of formula I-XXV, as well as inclusion of otheractive agents, and pharmaceutically acceptable carriers, excipients,emollients, stabilizers, etc., as are known in the pharmaceuticalindustry. In some embodiments, the term “consisting essentially of”refers to a composition, whose only active ingredient is the indicatedactive ingredient, however, other compounds may be included which arefor stabilizing, preserving, etc. the formulation, but are not involveddirectly in the therapeutic effect of the indicated active ingredient.In some embodiments, the term “consisting essentially of” may refer tocomponents which facilitate the release of the active ingredient. Insome embodiments, the term “consisting” refers to a composition, whichcontains the active ingredient and a pharmaceutically acceptable carrieror excipient.

In one embodiment, the present invention provides combined preparations.In one embodiment, the term “a combined preparation” defines especiallya “kit of parts” in the sense that the combination partners as definedabove can be dosed independently or by use of different fixedcombinations with distinguished amounts of the combination partnersi.e., simultaneously, concurrently, separately or sequentially. In someembodiments, the parts of the kit of parts can then, e.g., beadministered simultaneously or chronologically staggered, that is atdifferent time points and with equal or different time intervals for anypart of the kit of parts. The ratio of the total amounts of thecombination partners, in some embodiments, can be administered in thecombined preparation. In one embodiment, the combined preparation can bevaried, e.g., in order to cope with the needs of a patient subpopulationto be treated or the needs of the single patient which different needscan be due to a particular disease, severity of a disease, age, sex, orbody weight as can be readily made by a person skilled in the art.

It is to be understood that this invention is directed to compositionsand combined therapies as described herein, for any disease, disorder orcondition, as appropriate, as will be appreciated by one skilled in theart. Certain applications of such compositions and combined therapieshave been described hereinabove, for specific diseases, disorders andconditions, representing embodiments of this invention, and methods oftreating such diseases, disorders and conditions in a subject byadministering a compound as herein described, alone or as part of thecombined therapy or using the compositions of this invention representadditional embodiments of this invention.

Biological Activity of Selective Androgen Modulator Compounds

In some embodiments, the compounds of this invention possess in vivotissue selective androgenic and anabolic activity, which is accordinglyutilized for particular applications, as will be appreciated by oneskilled in the art.

In one embodiment, the methods of this invention are useful a subject,which is a human. In another embodiment, the subject is a mammal. Inanother embodiment the subject is an animal. In another embodiment thesubject is an invertebrate. In another embodiment the subject is avertebrate. In one embodiment, the subject is a feedlot animal, a beefcattle and/or a finishing livestock.

In one embodiment, the subject is male. In another embodiment, thesubject is female. In some embodiments, while the methods as describedherein may be useful for treating either males or females, females mayrespond more advantageously to administration of certain compounds, forcertain methods, as described and exemplified herein.

In another embodiment of the present invention, a method is provided forhormonal therapy in a patient (i.e., one suffering from anandrogen-dependent condition) which includes contacting an androgenreceptor of a patient with a compound and/or a non steroidal agonist ofthe present invention and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, hydrate, N-oxide or any combination thereof, in anamount effective to bind the compound to the androgen receptor andeffect a change in an androgen-dependent condition.

In one embodiment of this invention, a method is provided for hormonereplacement therapy in a patient (i.e., one suffering from anandrogen-dependent condition) which includes administering a compound asherein described and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, hydrate, N-oxide or any combination thereof, to asubject, in an amount sufficient to effect a change in ahormone-dependent condition in the subject.

In one embodiment, this invention provides for the use of a compound asherein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for a) accelerate bone repair; b) treating bone disorders; c)treating bone density loss; d) treating low bone mineral density (BMD);e) treating reduced bone mass; f) treating metabolic bone disease; g)promoting bone growth or regrowth; h) promoting bone restoration; i)promoting bone fracture repair; j) promoting bone remodeling; k)treating bone damage following reconstructive surgery including of theface, hip, or joints; l) enhancing of bone strength and function; m)increasing cortical bone mass; n) increasing trabecular connectivity.

In one embodiment, the bone related disorder is a genetic disorder, orin another embodiment, is induced as a result of a treatment regimen fora given disease. For example, and in one embodiment, the compounds asherein described are useful in treating a bone-related disorder thatarises as a result of cancer metastasis to bone, or in anotherembodiment, as a result of androgen-deprivation therapy, for example,given in response to prostate carcinogenesis in the subject.

In one embodiment, the bone-related disorder is osteoporosis. In anotherembodiment, the bone-related disorder is osteopenia. In anotherembodiment, the bone-related disorder is increased bone resorption. Inanother embodiment, the bone-related disorder is bone fracture. Inanother embodiment, the bone-related disorder is bone frailty.

In another embodiment, the bone-related disorder is a loss of bonemineral density (BMD). In another embodiment, the bone-related disorderis any combination of osteoporosis, osteopenia, increased boneresorption, bone fracture, bone frailty and loss of BMD. Each disorderrepresents a separate embodiment of the present invention.

“Osteoporosis” refers, in one embodiment, to a thinning of the boneswith reduction in bone mass due to depletion of calcium and boneprotein. In another embodiment, osteoporosis is a systemic skeletaldisease, characterized by low bone mass and deterioration of bonetissue, with a consequent increase in bone fragility and susceptibilityto fracture. In osteoporotic patients, bone strength is abnormal, in oneembodiment, with a resulting increase in the risk of fracture. Inanother embodiment, osteoporosis depletes both the calcium and theprotein collagen normally found in the bone, in one embodiment,resulting in either abnormal bone quality or decreased bone density. Inanother embodiment, bones that are affected by osteoporosis can fracturewith only a minor fall or injury that normally would not cause a bonefracture. The fracture can be, in one embodiment, either in the form ofcracking (as in a hip fracture) or collapsing (as in a compressionfracture of the spine). The spine, hips, and wrists are common areas ofosteoporosis-induced bone fractures, although fractures can also occurin other skeletal areas. Unchecked osteoporosis can lead, in anotherembodiment, to changes in posture, physical abnormality, and decreasedmobility.

In one embodiment, the osteoporosis results from androgen deprivation.In another embodiment, the osteoporosis follows androgen deprivation. Inanother embodiment, the osteoporosis is primary osteoporosis. In anotherembodiment, the osteoporosis is secondary osteoporosis. In anotherembodiment, the osteoporosis is postmenopausal osteoporosis. In anotherembodiment, the osteoporosis is juvenile osteoporosis. In anotherembodiment, the osteoporosis is idiopathic osteoporosis. In anotherembodiment, the osteoporosis is senile osteoporosis.

In one embodiment, the methods of this invention are useful in treatingdiseases or disorders caused by, or associated with a hormonal disorder,disruption or imbalance. In one embodiment, the hormonal disorder,disruption or imbalance comprises an excess of a hormone. In anotherembodiment, the hormonal disorder, disruption or imbalance comprises adeficiency of a hormone. In one embodiment, the hormone is a steroidhormone. In another embodiment, the hormone is an estrogen. In anotherembodiment, the hormone is an androgen. In another embodiment, thehormone is a glucocorticoid. In another embodiment, the hormone is acortico-steroid. In another embodiment, the hormone is LuteinizingHormone (LH). In another embodiment, the hormone is Follicle StimulatingHormone (FSH). In another embodiment, the hormone is any other hormoneknown in the art. In another embodiment, the hormonal disorder, isdisruption or imbalance is associated with menopause. In anotherembodiment, the hormonal disorder, disruption or imbalance is associatedwith andropause, andropausal vasomotor symptoms, andropausalgynecomastia, muscle strength and/or function, bone strength and/orfunction and anger. In another embodiment, hormone deficiency is aresult of specific manipulation, as a byproduct of treating a disease ordisorder in the subject. For example, the hormone deficiency may be aresult of androgen depletion in a subject, as a therapy for prostatecancer in the subject. Each possibility represents a separate embodimentof the present invention.

In another embodiment the invention is directed to treating sarcopeniaor cachexia, and associated conditions related thereto, for examplediseases or disorders of the bone.

In one embodiment, this invention provides for the use of a compound asherein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for 1) treating a muscle wasting disorder; 2) preventing amuscle wasting disorder; 3) treating, preventing, suppressing,inhibiting or reducing muscle loss due to a muscle wasting disorder; 4)treating, preventing, inhibiting, reducing or suppressing muscle wastingdue to a muscle wasting disorder; and/or 5) treating, preventing,inhibiting, reducing or suppressing muscle protein catabolism due to amuscle wasting disorder; and/or treating, preventing, inhibiting,reducing or suppressing end stage renal disease; and/or 6) treating,preventing, inhibiting, reducing or suppressing frailty.

In another embodiment, the use of a compound for treating a subjecthaving a muscle wasting disorder, or any of the disorders describedherein, includes administering a pharmaceutical composition including acompound as herein described. In another embodiment, the administeringstep includes intravenously, intraarterially, or intramuscularlyinjecting to said subject said pharmaceutical composition in liquidform; subcutaneously implanting in said subject a pellet containing saidpharmaceutical composition; orally administering to said subject saidpharmaceutical composition in a liquid or solid form; or topicallyapplying to the skin surface of said subject said pharmaceuticalcomposition.

A muscle is a tissue of the body that primarily functions as a source ofpower. There are three types of muscles in the body: a) skeletalmuscle—the muscle responsible for moving extremities and external areasof the bodies; b) cardiac muscle—the heart muscle; and c) smoothmuscle—the muscle that is in the walls of arteries and bowel.

A wasting condition or disorder is defined herein as a condition ordisorder that is characterized, at least in part, by an abnormal,progressive loss of body, organ or tissue mass. A wasting condition canoccur as a result of a pathology such as, for example, cancer, or aninfection, or it can be due to a physiologic or metabolic state, such asdisuse deconditioning that can occur, for example, due to prolonged bedrest or when a limb is immobilized, such as in a cast. A wastingcondition can also be age associated. The loss of body mass that occursduring a wasting condition can be characterized by a loss of total bodyweight, or a loss of organ weight such as a loss of bone or muscle massdue to a decrease in tissue protein.

In one embodiment, “muscle wasting” or “muscular wasting”, used hereininterchangeably, refer to the progressive loss of muscle mass and/or tothe progressive weakening and degeneration of muscles, including theskeletal or voluntary muscles which control movement, cardiac muscleswhich control the heart, and smooth muscles. In one embodiment, themuscle wasting condition or disorder is a chronic muscle wastingcondition or disorder. “Chronic muscle wasting” is defined herein as thechronic (i.e. persisting over a long period of time) progressive loss ofmuscle mass and/or to the chronic progressive weakening and degenerationof muscle.

The loss of muscle mass that occurs during muscle wasting can becharacterized by a muscle protein breakdown or degradation, by muscleprotein catabolism. Protein catabolism occurs because of an unusuallyhigh rate of protein degradation, an unusually low rate of proteinsynthesis, or a combination of both. Protein catabolism or depletion,whether caused by a high degree of protein degradation or a low degreeof protein synthesis, leads to a decrease in muscle mass and to musclewasting. The term “catabolism” has its commonly known meaning in theart, specifically an energy burning form of metabolism.

Muscle wasting can occur as a result of a pathology, disease, conditionor disorder. In one embodiment, the pathology, illness, disease orcondition is chronic. In another embodiment, the pathology, illness,disease or condition is genetic. In another embodiment, the pathology,illness, disease or condition is neurological. In another embodiment,the pathology, illness, disease or condition is infectious. As describedherein, the pathologies, diseases, conditions or disorders for which thecompounds and compositions of the present invention are administered arethose that directly or indirectly produce a wasting (i.e. loss) ofmuscle mass, that is a muscle wasting disorder.

In one embodiment, muscle wasting in a subject is a result of thesubject having a muscular dystrophie; muscle atrophy; X-linkedspinal-bulbar muscular atrophy (SBMA).

The muscular dystrophies are genetic diseases characterized byprogressive weakness and degeneration of the skeletal or voluntarymuscles that control movement. The muscles of the heart and some otherinvoluntary muscles are also affected in some forms of musculardystrophy. The major forms of muscular dystrophy (MD) are: duchennemuscular dystrophy, myotonic dystrophy, becker muscular dystrophy,limb-girdle muscular dystrophy, facioscapulhumeral muscular dystrophy,congenital muscular dystrophy, oculopharyngeal muscular dystrophy,distal muscular dystrophy and emery-dreifuss muscular dystrophy.

Muscular dystrophy can affect people of all ages. Although some formsfirst become apparent in infancy or childhood, others may not appearuntil middle age or later. Duchenne Md. is the most common form,typically affecting children. Myotonic dystrophy is the most common ofthese diseases in adults.

Muscle atrophy (MA) is characterized by wasting away or diminution ofmuscle and a decrease in muscle mass. For example, Post-Polio MA is amuscle wasting that occurs as part of the post-polio syndrome (PPS). Theatrophy includes weakness, muscle fatigue, and pain.

Another type of MA is X-linked spinal-bulbar muscular atrophy (SBMA—alsoknown as Kennedy's Disease). This disease arises from a defect in theandrogen receptor gene on the X chromosome, affects only males, and itsonset is in adulthood. Because the primary disease cause is an androgenreceptor mutation, androgen replacement is not a current therapeuticstrategy. There are some investigational studies where exogenoustestosterone propionate is being given to boost the levels of androgenwith hopes of overcoming androgen insensitivity and perhaps provide ananabolic effect. Still, use of supraphysiological levels of testosteronefor supplementation will have limitations and other potentially seriouscomplications.

Sarcopenia is a debilitating disease that afflicts the elderly andchronically ill patients and is characterized by loss of muscle mass andfunction. Further, increased lean body mass is associated with decreasedmorbidity and mortality for certain muscle-wasting disorders. Inaddition, other circumstances and conditions are linked to, and cancause muscle wasting disorders. For example, studies have shown that insevere cases of to chronic lower back pain, there is paraspinal musclewasting.

Muscle wasting and other tissue wasting is also associated with advancedage. It is believed that general weakness in old age is due to musclewasting. As the body ages, an increasing proportion of skeletal muscleis replaced by fibrous tissue. The result is a significant reduction inmuscle power, performance and endurance.

In another embodiment, muscle wasting or other tissue wasting may be aresult of alcoholism, and may be treated with the compounds andcompositions of the invention, representing embodiments thereof.

In one embodiment, the invention provides a use of SARM compound asdescribed herein or its prodrug, analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, N-oxide, hydrate or any combination thereof for thetreatment of a wasting disease, disorder or condition in a subject.

In one embodiment, the wasting disease, disorder or condition beingtreated is associated with chronic illness

This invention is directed to treating, in some embodiments, any wastingdisorder, which may be reflected in muscle wasting, weight loss,malnutrition, starvation, or any wasting or loss of functioning due to aloss of tissue mass.

In some embodiments, wasting diseases or disorders, such as cachexia;malnutrition, tuberculosis, leprosy, diabetes, renal disease, chronicobstructive pulmonary disease (COPD), cancer, end stage renal failure,sarcopenia, emphysema, osteomalacia, or cardiomyopathy, may be treatedby the methods of this invention, via the administration of a SARMcompound as herein described, compositions comprising the same, with orwithout additional drugs, compounds, or agents, which provide atherapeutic effect for the condition being treated.

In some embodiments, wasting is due to infection with enterovirus,Epstein-Barr virus, herpes zoster, HIV, trypanosomes, influenze,coxsackie, rickettsia, trichinella, schistosoma or mycobacteria, andthis invention, in some embodiments, provides methods of treatmentthereof.

Cachexia is weakness and a loss of weight caused by a disease or as aside effect of illness. Cardiac cachexia, i.e. a muscle protein wastingof both the cardiac and skeletal muscle, is a characteristic ofcongestive heart failure. Cancer cachexia is a syndrome that occurs inpatients with solid tumors and hematological malignancies and ismanifested by weight loss with massive depletion of both adipose tissueand lean muscle to mass.

Cachexia is also seen in acquired immunodeficiency syndrome (AIDS),human immunodeficiency virus (HIV)-associated myopathy and/or muscleweakness/wasting is a relatively common clinical manifestation of AIDS.Individuals with HIV-associated myopathy or muscle weakness or wastingtypically experience significant weight loss, generalized or is proximalmuscle weakness, tenderness, and muscle atrophy.

In one embodiment, “Hypogonadism” is a condition resulting from orcharacterised by abnormally decreased functional activity of the gonads,with retardation of growth and sexual development.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a wastingdisease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and anti-cancer agent, an immunomodulating agent, anantidiabetic agent, an agent treating the cardiovascular system, anagent treating the gastrointestinal system, an agent treating thecentral nervous system, an agent treating a metabolic disease, an agenttreating a wasting disease, a gene therapy agent, an agent treating theendocrine system, vitamins, or a combination thereof. In someembodiments, wasting diseases comprise muscle injury, bed rest,immobility, nerve injury, neuropathy, diabetic neuropathy, alcoholicneuropathy, subacute combined degeneration of the spinal cord, diabetes,rheumatoid arthritis, motor neurone diseases, Duchenne musculardystrophy, carpal tunnel syndrome, chronic infection, tuberculosis,Addison's disease, adult sma, limb muscle atrophy, alcoholic neuropathy,anorexia, anorexia nervosa, anorexia associated with cachexia, anorexiaassociated with aging, back tumour, dermatomyositis, hip cancer,inclusion body myositis, incontinentia pigmenti, intercostal neuralgia,juvenile rheumatoid arthritis, Legg-Calve-Perthes disease, muscleatrophy, multifocal motor neuropathy, nephrotic syndrome, osteogenesisimperfecta, post-polio syndrome, rib tumor, spinal muscular atrophy,reflex sympathetic dystrophy syndrome, or Tay-Sachs.

A wasting condition or disorder is defined herein as a condition ordisorder that is characterized, at least in part, by an abnormal,progressive loss of body, organ or tissue mass. A wasting condition canoccur as a result of a pathology such as, for example, cancer, or it canbe due to a physiologic or metabolic state, such as disusedeconditioning that can occur, for example, due to prolonged bed rest orwhen a limb is immobilized, such as in a cast, or with the occurrence ofmultiple wounds, including, for example, amputation, as occurs indiabetics, and other conditions, as will be appreciated by one skilledin the art. A wasting condition can also be age associated. The loss ofbody mass that occurs during a wasting condition can be characterized bya loss of total body weight, or a loss of organ weight such as a loss ofbone or muscle mass due to a decrease in tissue protein.

In one embodiment, the terms “muscle wasting” or “muscular wasting”,refer to the progressive loss of muscle mass and/or to the progressiveweakening and is degeneration of muscles, including the skeletal orvoluntary muscles which control movement, cardiac muscles which controlthe heart, and smooth muscles. In one embodiment, the muscle wastingcondition or disorder is a chronic muscle wasting condition or disorder.“Chronic muscle wasting” is defined herein as the chronic (i.e.persisting over a long period of time) progressive loss of muscle massand/or to the chronic progressive weakening and degeneration of muscle.

The loss of muscle mass that occurs during muscle wasting can becharacterized by a muscle protein breakdown or degradation, by muscleprotein catabolism. Protein catabolism occurs because of an unusuallyhigh rate of protein degradation, an unusually low rate of proteinsynthesis, or a combination of both. Protein catabolism or depletion,whether caused by a high degree of protein degradation or a low degreeof protein synthesis, leads to a decrease in muscle mass and to musclewasting. The term “catabolism” has its commonly known meaning in theart, specifically an energy burning form of metabolism.

Muscle wasting can occur as a result of pathology, disease, condition ordisorders, including disorders for treatment via the methods of thisinvention, such as, for example, end stage renal failure.

In one embodiment, the wasting disease is cachexia or involuntary weightloss in a subject. In another embodiment, the present invention providesa method of treating, preventing, inhibiting, reducing or suppressingmuscle wasting in a subject suffering from a kidney disease. In oneembodiment, the present invention provides a method of treating,preventing, inhibiting, reducing or suppressing protein catabolism in asubject suffering from a kidney disease or disorder,

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a hypogonadalstate in a subject. In one embodiment, the present invention provides amethod for treating, reducing the incidence, delaying the onset orprogression, or reducing and/or abrogating the symptoms associated witha pharmacotherapy induced hypogonadal state in a subject. In someembodiments, hypogonadism is caused by treatments which alter thesecretion of hormones from the sex to glands in both women and men. Insome embodiments, hypogonadism may be “primary” or “central”. In primaryhypogonadism, the ovaries or testes themselves do not function properly.In some embodiments, hypogonadism may be induced by surgery, radiation,genetic and developmental disorders, liver and kidney disease,infection, or certain autoimmune disorders. In some embodiments,menopause is a form of hypogonadism.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a combination ofdiseases and/or disorders in a subject as described hereinabove. In oneembodiment, the method comprises administering to a subject acomposition comprising a compound of this invention and an anti-canceragent, an immunomodulating agent, an antidiabetic agent, an agenttreating the cardiovascular system, an agent treating thegastrointestinal system, an agent treating the central nervous system,an agent treating a metabolic disease, an agent treating a wastingdisease, a gene therapy agent, an agent treating the endocrine system,an agent treating a dermatological disorder, an anti-infective agent, anagent treating the liver, an agent treating the kidney, vitamins, or acombination thereof.

It is to be understood that any method of this invention, as hereindescribed, encompasses the administration of a compound as hereindescribed, or a composition comprising the same, to the subject, inorder to treat the indicated disease, disorder or condition. The methodsas herein described each and/or all may further comprise administrationof an additional therapeutic agent as herein described, and as will beappreciated by one skilled in the art.

In some embodiments, the present invention provides a method forenhanced production such as milk, sperm, or egg. In some embodiments,the present invention provides a method for enhanced production of leanmeats or eggs. In some embodiments, the present invention provides amethod for increased productivity of feeds or stud livestock, forexample, increased sperm count, improved morphology of sperm, etc. Insome embodiments, the present invention provides a method for expandingthe productive life of farm animals, for example, egg-laying hens,milk-producing cows, etc, and/or enhanced herd health, for example,improved immune clearance, stronger animals.

In another embodiment, the compounds of this invention and compositionsas described herein are useful in promoting or speeding recoveryfollowing a surgical procedure.

In one embodiment, the present invention provides a use of a compound asto described herein for reducing a fat mass in a subject. In anotherembodiment the invention provides such methods for use of the compoundas described herein or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, or a composition comprising the same.

In one embodiment, the present invention provides a use of a compound asdescribed herein for increasing a lean mass in a subject. In anotherembodiment such use comprises administration of a compound as describedherein or its prodrug, analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, N-oxide, hydrate or any combination thereof.

In one embodiment the subject has a hormonal imbalance, disorder, ordisease. In another embodiment the subject has menopause.

Example 4 demonstrates that a compound of formula (S-II) is anabolic yetminimally androgenic, thus such compounds may be useful in treatingpatient groups in which androgens were contraindicated in the past.Compound of formula (S-II) was shown to stimulate muscle growth, whetherin the presence or absence of testosterone while exertinganti-proliferative effects on the prostate, thus, in one embodiment, themethods of this invention provide for restoring lost muscle mass inpatients with sarcopenia or cachexia.

In one embodiment, the compounds as herein described alter the levels ofleptin in a subject. In another embodiment, the compounds as hereindescribed decrease the levels of leptin. In another embodiment, thecompounds as herein described increase the levels of leptin in asubject. Leptin is known to have an effect on appetite on weight loss inobese mice, and thus has been implicated in obesity.

The compounds as herein described, in one embodiment, affectcirculating, or in another embodiment, tissue levels of leptin. In oneembodiment, the term ‘level/s of leptin’ refers to the serum level ofleptin. As contemplated herein, the compounds of the present inventionhave an effect on leptin in vitro and in vivo. Leptin levels can bemeasured by methods known to one skilled in the art, for example bycommercially available ELISA kits. In addition, Leptin levels may bedetermined in in vitro assays, or in in vivo assays, by any method knownto a person skilled in the art.

Since leptin is implicated in controlling appetite, weight loss, foodintake, and energy expenditure, modulating and/or controlling the levelsof leptin is a useful therapeutic approach in treating preventing,inhibiting or reducing the incidence of obesity in subjects sufferingfrom obesity. Modulating the level of leptin can result in a loss ofappetite, a reduction of food intake, and an increase in energyexpenditure in the subject, and thus may contribute to the control andtreatment of obesity.

The term “obesity” is defined, in one embodiment, as an increase in bodyweight beyond the limitation of skeletal and physical requirement, asthe result of excessive accumulation of fat in the body.

The term “obesity-associated metabolic disorder” refers, in oneembodiment, to a disorder which results from, is a consequence of, isexacerbated by or is secondary to obesity. Non-limiting examples of sucha disorder are osteoarthritis, Type II diabetes mellitus, increasedblood pressure, stroke, and heart disease.

In addition, androgens have recently been shown to be involved incommitment of mesenchymal pluripotent cells into myogenic lineage and toblock differentiation into adipogenic lineage (Singh et al.,Endocrinology, 2003, Jul. 24). Accordingly, the compounds can be usefulin methods of blocking adipogenesis, and/or altering stem celldifferentiation, as described herein.

In another embodiment, this invention relates to a method of decreasing,suppressing, inhibiting or reducing appetite of a subject, comprisingthe step of administering to the subject a compound as herein describedand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug,polymorph, crystal, or any combination thereof, in an amount effectiveto decrease, suppress, inhibit or reduce the appetite of the subject.

In another embodiment, this invention relates to a method of alteringthe body composition of a subject, comprising the step of administeringto the subject a compound as herein described and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal,or any combination thereof, in an amount effective to alter the bodycomposition of the subject. In one embodiment, altering the bodycomposition comprises altering the lean body mass, the fat free bodymass of the subject, or a combination thereof.

In another embodiment, this invention relates to a method of alteringlean body mass or fat free body mass of a subject, comprising the stepof administering to the subject a compound as herein described and/orits analog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph,crystal, or any combination thereof, in an amount effective to alter thelean body mass or fat free body mass of the subject.

In another embodiment, this invention relates to a method of convertingfat to lean muscle in a subject, comprising the step of administering tothe subject a compound as herein described and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal,or any combination thereof, in an amount effective to convert fat tolean muscle in the subject.

It is to be understood that any use of any of the compounds as herein isdescribed may be used in the treatment of any disease, disorder orcondition as described herein, and represents an embodiment of thisinvention.

The following examples are presented in order to more fully illustratethe preferred embodiments of the invention. They should in no way,however, be construed as limiting the broad scope of the invention.

EXAMPLES Example 1 Synthesis of (S) Enantiomer of Compound of Formula II

(2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid

D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH andcooled in an ice bath; the resulting alkaline solution was diluted withacetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride(13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneouslyadded over 40 min to the aqueous solution of D-proline in an ice bath.The pH of the mixture was kept at 10-11° C. during the addition of themethacryloyl chloride. After stirring (3 h, room temperature), themixture was evaporated in vacuo at a temperature at 35-45° C. to removeacetone. The resulting solution was washed with ethyl ether and wasacidified to pH 2 with concentrated HCl. The acidic mixture wassaturated with NaCl and was extracted with EtOAc (100 mL×3). Thecombined extracts were dried over Na₂SO₄, filtered through Celite, andevaporated in vacuo to give the crude product as a colorless oil.Recrystallization of the oil from ethyl ether and hexanes afforded 16.2g (68%) of the desired compound as colorless crystals: mp 102-103° C.(lit. [214] mp 102.5-103.5° C.); the NMR spectrum of this compounddemonstrated the existence of two rotamers of the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15(s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers,vinyl CH₂), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for thesecond rotamer (totally 1H for both rotamers, CH at the chiral canter),3.57-3.38 (m, 2H, CH₂), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH₂, CH,Me); ¹³C NMR (75 MHz, DMSO-d₆) δ for major rotamer 173.3, 169.1, 140.9,116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0,141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737(C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm⁻¹; [α]_(D)²⁶+80.8° (c=1, MeOH); Anal. Calcd. for C₉H₁₃NO₃: C, 59.00; H, 7.15; N,7.65. Found: C, 59.13; H, 7.19; N, 7.61.

(3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-dione

A solution of NBS (23.5 g, 0.132 mol) in 100 mL of DMF was addeddropwise to a stirred solution of the (methyl-acryloyl)-pyrrolidine(16.1 g, 88 mmol) in 70 mL of DMF under argon at room temperature, andthe resulting mixture was stirred 3 days. The solvent was removed invacuo, and a yellow solid was precipitated. The solid was suspended inwater, stirred overnight at room temperature, filtered, and dried togive 18.6 g (81%) (smaller weight when dried ˜34%) of the title compoundas a yellow solid: mp 152-154° C. (lit. [214] mp 107-109° C. for theS-isomer); ¹H NMR (300 MHz, DMSO-d₆) δ 4.69 (dd, J=9.6 Hz, J=6.7 Hz, 1H,CH at the chiral center), 4.02 (d, J=11.4 Hz, 1H, CHH_(a)), 3.86 (d,J=11.4 Hz, 1H, CHH_(b)), 3.53-3.24 (m, 4H, CH₂), 2.30-2.20 (m, 1H, CH),2.04-1.72 (m, 3H, CH₂ and CH), 1.56 (s, 2H, Me); ¹³C NMR (75 MHz,DMSO-d₆) δ 167.3, 163.1, 83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR(KBr) 3474, 1745 (C═O), 1687 (C═O), 1448, 1377, 1360, 1308, 1227, 1159,1062 cm⁻¹; [α]_(D) ²⁶+124.5° (c=1.3, chloroform); Anal. Calcd. forC₉H₁₂BrNO₃: C, 41.24; H, 4.61; N, 5.34. Found: C, 41.46; H, 4.64; N,5.32.

(2R)-3-Bromo-2-hydroxy-2-methylpropanoic Acid

A mixture of bromolactone (18.5 g, 71 mmol) in 300 mL of 24% HBr washeated at reflux for 1 h. The resulting solution was diluted with brine(200 mL), and was extracted with ethyl acetate (100 mL×4). The combinedextracts were washed with saturated NaHCO₃ to (100 mL×4). The aqueoussolution was acidified with concentrated HCl to pH=1, which, in turn,was extracted with ethyl acetate (100 mL×4). The combined organicsolution was dried over Na₂SO₄, filtered through Celite, and evaporatedin vacuo to dryness. Recrystallization from toluene afforded 10.2 g(86%) of the desired compound as colorless crystals: mp 107-109° C.(lit. [214] mp 109-113° C. for the S-isomer); ¹H NMR (300 MHz, DMSO-d₆)δ 3.63 (d, J=10.1 Hz, 1H, CHH_(a)), 3.52 (d, J=10.1 Hz, 1H, CHH_(b)),1.35 (s, 3H, Me); IR (KBr) 3434 (OH), 3300-2500 (COOH), 1730 (C═O),1449, 1421, 1380, 1292, 1193, 1085 cm⁻¹; [α]_(D) ²⁶+10.5° (c=2.6, MeOH);Anal. Calcd. for C₄H₇BrO₃: C, 26.25; H, 3.86. Found: C, 26.28; H, 3.75.

Synthesis of(2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide

Thionyl chloride (46.02 g, 0.39 mol) was added dropwise to a cooledsolution (less than 4° C.) of R-18 (51.13 g, 0.28 mol) in 300 mL of THFunder an argon atmosphere. The resulting mixture was stirred for 3 hunder the same condition. To this was added Et₃N (39.14 g, 0.39 mol) andstirred for 20 min under the same condition. After 20 min,5-amino-2-cyanobenzotrifluoride (40.0 g, 0.21 mol), 400 mL of THF wereadded and then the mixture was allowed to stir overnight at roomtemperature. The solvent was removed under reduced pressure to give asolid which was treated with 300 mL of H₂O, extracted with EtOAc (2×400mL). The combined organic extracts were washed with saturated NaHCO₃solution (2×300 mL) and brine (300 mL). The organic layer was dried overMgSO₄ and concentrated under reduced pressure to give a solid, which waspurified from column chromatography using CH₂Cl₂/EtOAc (80:20) to give asolid. This solid was recrystallized from CH₂Cl₂/hexane to give 55.8 g(73.9%) of(2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide(R-19) as a light-yellow solid.

¹H NMR (CDCl₃/TMS) δ 1.66 (s, 3H, CH₃), 3.11 (s, 1H, OH), 3.63 (d,J=10.8 Hz, 1H, CH₂), 4.05 (d, J=10.8 Hz, 1H, CH₂), 7.85 (d, J=8.4 Hz,1H, ArH), 7.99 (dd, J=2.1, 8.4 Hz, 1H, ArH), 8.12 (d, J=2.1 Hz, 1H,ArH), 9.04 (bs, 1H, NH). Calculated Mass: 349.99, [M-H]⁻ 349.0. M.p.:124-126° C.

Synthesis of(S)-3-(4-chloro-3-fluorophenoxy)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide

A mixture of bromoamide((2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide,(R-19) 2.0 g, 5.70 mmol) and anhydrous K₂CO₃ (2.4 g, 17.1 mmol) washeated to reflux for 2 h and then concentrated under reduced pressure togive a solid. The resulting solid was treated with4-chloro-3-fluorophenol (1.3 g, 8.5 mmol) and anhydrous K₂CO₃ (1.6 g,11.4 mmol) in 50 mL of 2-propanol and was heated to reflux for 3 h, thenconcentrated under reduced pressure to give a solid. The residue wastreated with 100 mL of H₂O and then extracted with EtOAc (2×100 mL). Thecombined EtOAc extracts were washed with 10% NaOH (4×100 mL) and brine,successively. The organic layer was dried over MgSO₄ and thenconcentrated under reduced pressure to give an oil which was purified bycolumn chromatography using EtOAc/hexane (50:50) to give a solid whichwas recrystallized from CH₂Cl₂/hexane to give 1.7 g (70.5%) of(S)-3-(4-chloro-3-fluorophenoxy)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamideas a colorless solid.

¹H NMR (CDCl₃/TMS) δ 1.60 (s, 3H, CH₃), 3.28 (s, 1H, OH), 3.98 (d,J=9.05 Hz, 1H, CH), 6.64-6.76 (m, 2H, ArH), 7.30 (d, J=8.67 Hz, 1H,ArH), 7.81 (d, J=8.52 Hz, 1H, ArH), 7.96 (q, J=2.07, 8.52 Hz, 1H, ArH),8.10 (d, J=2.07 Hz, 1H, ArH), 9.10 (s, 1H, NH). Calculated Mass: [M-H]⁻414.9. Mp: 132-134° C.

Example 2 Metabolic Stability of the Compounds of this Invention

Metabolic stability assays were performed in order to assess the invitro half-life of compounds of formula II when incubated with humanliver microsomes. The data generated was transformed to determineintrinsic clearance values. In a separate experiment, permeabilityacross human, intestinal epithelial monolayers (Caco-2 cells) was usedas a measure of intestinal permeability as well as an indicator ofefflux potential. Caco-2 cells are often used as an early screeningsurrogate for oral bioavailability. Microsomal half-life can beconverted to in vitro clearance values as a means to predict hepaticintrinsic clearance. Intrinsic clearance is defined as the functionalability of the liver to metabolize a drug or other compound.

Materials and Methods:

Metabolic Stability Measured in Human Liver Microsomes:

Compound of formula S-II in this study was incubated at a finalconcentration concentration of 0.6 μM. Microsome reactions wereperformed under either Phase I or “Phase I and II” conditions, whereindicated. Compound stocks (10 mM ACN) were initially initially dilutedto a concentration of 60 μM (in 60% ACN/H₂O) resulting in a “workingstock” stock” solution of 100×. Human liver microsomes were utilized ata final concentration of 0.6 mg/ml. Duplicate wells were used for eachtime point (0, 6, 10, 30, and 60 minutes). Reactions were carried out at37° C. in a shaking water bath, and the final concentration of solventwas kept constant at 0.6%. The final volume for each reaction was 600μl, comprised of 368 μl of 100 mM KPO₄ buffer, (pH 7.4); 12.6 μl of HLM(from a 20 mg/ml stock); 6 μl of 100×“working stock” drug compound, and126 μl of NRS “master mix” solution. At each time point, 100 μl ofreaction was removed and added to a sample well containing 100 μl ofice-cold, 100% ACN (plus internal standards), to stop the reaction. TheNRS “master mix” is a solution of glucose-6-phosphate dehydrogenase,NADP⁺, MgCl₂, and glucose-6-phosphate, prepared per manufacturer'sinstructions (BD Biosciences, Waltham, Mass.). Each 6.0 ml stock of NRS“master mix” solution contains 3.8 3.8 ml H₂O, 1.0 ml solution “A” (Cat.#461220), and 0.2 ml solution “B” (Cat. #461200). Human liver microsomes(lot #0610279, Xenotech Corp.) represented a pool of 60 donors. donors.

Samples were centrifuged at 3,000 rpm for 10 minutes at 4° C. to removedebris and precipitate protein. Approximately 160 μl of supernatant wassubsequently transferred to a new sample block for analysis. Theconcentration of parent drug remaining in each well (expressed aspercent remaining versus Time ‘0’, at the beginning of the reaction) wasmeasured by LC/MS, as detailed below. The intrinsic clearance rates(CLint) were calculated from 0-60 minutes based on first order decaykinetics as a is function of microsomal protein concentration.

Permeability Across Human, Intestinal Epithelial Monolayers:

Permeability was measured in the Apical (pH 6.6) to Basolateral (pH 7.4)and Basolateral (pH 7.4) to Apical (pH 6.6) directions across polarized,Caco-2 epithelial monolayers. Compound stocks (10 mM acetonitrile) weretested in the study at a final concentration of 10 μM. The concentrationof drug in the receiver well was measured by LC/MS/MS using a standardcurve. The apparent permeability (Papp) for each compound wascalculated, and values (A-B) were classified as: Poor (Papp: <1), Low(Papp 1-2), Medium (Papp 2-10) or High (Papp>10).Papp(×10⁻⁶ cm/sec)=Amount transported/(Area*Initial concentration*Time)Papp(cm/s)=[V/(A*Ci)]*(Cf/T)V=volume of the receptor chamber (ml, or cm³)A=area of the membrane insert (cm²)Ci=initial concentration of drug (μM)Cf=final concentration of drug (μM)T=assay time (seconds)Analytical Methods:

All samples were analyzed on the MDS/Sciex API4000 Q Trap system withelectrospray ionization (ESI) in the positive or negative SIM mode,depending on the compounds. The mobile phases were isocratic at 30% A(0.1% formic acid in water) and 70% B (0.1% formic acid in acetonitrile)with a flow rate of 0.4 mL/min. A Phenomenex Luna Phenyl-Hexyl column(60×2.0 mm ID, 6μ) was used. The injection volume was 10 μL. The totalrun time per sample was 1.6 to 3.0 minutes. Tamoxifen and diclofenacwere used as internal standards for the positive and negative mode,respectively. The percentage of parent drug compound remaining aftereach time point was determined relative to the initial measuredconcentration at the beginning of the reaction (T₀ min).

Data Analysis:

For half-life determination, data was fitted using GraphPad Prism, v4.03 with the non-linear regression equation “one phase exponentialdecay” defined as: Y=Span*exp(−K*X)+Plateau (decays to Plateau with afirst-order rate constant, K). “−K” is the slope of the curve. The halflife (minutes), T_(1/2), =In 2/−K and is therefore defined as −0.693/K,a/k/a−0.693/slope). Intrinsic Clearance (μl/min/mg protein) is definedas: CLint=0.693*(1/T_(1/2))*(ml incubation/mg protein)*1000; Thisequation can also be expressed as (K*1000)/microsome concentration.

Results:

TABLE 1 Metabolic Stability Measured in Human Liver Microsomes: CL_(int)Compound Half Life (ul/min/mg) Half Life CL_(int) having (minutes) PhaseI (minutes) (ul/min/mg) formula Phase I only only Phase I + II Phase I +II S-II Stable <1 Stable <1

The results had shown that in vitro half-life as determined from themicrosomal assays demonstrated that compound of formula S-II under bothphase I and phase I/II metabolic conditions. As shown in Table 1, thecompound didn't exhibit an intrinsic clearance (CLint) value greaterthan 10 μl/min/mg. It is generally accepted that an in vitro CLint valueof less than 10 μl/min/mg protein represents favorable metabolicstability of the test compound. Compound of formula S-II exhibited lowclearance in human liver microsomes. In conclusion, based on the datareported herein, compound of formula S-II exhibited favorable metabolicstability profiles in vivo studies.

Example 3 Androgen Receptor Binding Affinity of SARMs

Materials and Methods:

The androgen receptor (AR) binding affinity of SARMs was determined byusing an in vitro competitive radioligand binding assay with[17α-methyl-³H]-Mibolerone ([³H]MIB, PerkinElmer), a high affinity ARligand. Recombinant androgen receptor ligand binding domain (AR LBD) wascombined with [³H]MIB in buffer A (10 mM Tris, pH 7.4, 1.6 mM disodiumEDTA, 0.26 M sucrose, 10 mM sodium molybdate, 1 mM PMSF) to determinethe equilibrium dissociation constant (K_(d)) of [³H]MIB. Protein wasincubated with increasing concentrations of [³H]MIB with and without ahigh concentration of unlabeled MIB in order to determine total andnon-specific binding. Non-specific binding was then subtracted fromtotal binding to determine specific binding and graphed using SigmaPlotand non-linear regression for ligand binding curve with one sitesaturation to determine the K_(d) of MIB (1.84 nM). In addition, theconcentration of [³H]MIB required to saturate AR LBD was determined tobe 4 nM.

Compound of formula S-II was tested in a range of concentrations from10⁻¹¹ to 10⁻⁶ M using the conditions described above. Followingincubation, plates were harvested with GF/B filters on the Unifilter-96Harvester (PerkinElmer) and washed three times with ice-cold buffer B(60 mM Tris, pH 7.2). The filter plates were dried at RT, then 36 μlMicroscint-O cocktail was added to each well and sealed with TopSeal-A.The receptor bound radioligand was then determined with the TopCount®NXT Microplate Scintillation Counter (PerkinElmer).

The specific binding of [³H]MIB at each concentration of SARM wasdetermined by subtracting the nonspecific binding of [³H]MIB (determinedby incubating with 10⁻⁶ M unlabeled MIB), and expressed as a percentageof the specific binding in the absence of each SARM. The concentrationof SARM required to decrease the [³H]MIB binding by 60%, IC₆₀ value, wasdetermined by computer-fitting the data with SigmaPlot and non-linearregression with the standard curve four parameter logistic curve. Theequilibrium binding constant (K_(i)) of each compound was thendetermined with the following equation:K _(i) =K _(d)×IC₆₀/(K _(d) +L)where K_(d) is the equilibrium dissociation constant of [³H]MIB (1.84nM), and L is the concentration of [³H]MIB (4 nM).

Results:

The binding affinity for compound of formula S-II was tested in theradioligand binding assay with AR LBD as the receptor with K_(i)(nM)=8.1.

Example 4 Preclinical Anabolic and Androgenic Pharmacology of Compoundof Formula (S-II) in Intact and Castrate Male Rats

Anabolic and androgenic efficacy of compound of formula S-IIadministered to by daily oral gavage were tested. The S-isomer ofcompound of formula II was synthesized and tested as described herein

Materials and Methods:

Male Sprague-Dawley rats weighing approximately 200 g were purchasedfrom Harlan Bioproducts for Science (Indianapolis, Ind.). The animalswere maintained on a 12-h light/dark cycle with food (7012C LM-485Mouse/Rat Sterilizable Diet, Harlan Teklad, Madison, Wis.) and wateravailable ad libitum. The animal protocol was reviewed and approved bythe Institutional Animal Care and Use Committee of the University ofTennessee. The anabolic and androgenic activity of the compound offormula S-II was studied in intact animals, acutely orchidectomized(ORX) animals and chronically (9 days) ORX rats.

The test article for this study was weighed and dissolved in 10% DMSO(Fisher) diluted with PEG 300 (Acros Organics, N.J.) for preparation ofthe appropriate dosage concentrations. The animals were housed in groupsof 2 to 3 animals per cage. Animals were randomly assigned to one ofseven groups consisting of 4 to 5 animals per group. Control groups(intact and ORX) were administered vehicle daily. Compound of formulaS-II was administered via oral gavage at doses of 0.01, 0.03, 0.1, 0.3,0.75, and 1 mg/day to both intact and ORX groups. Where appropriate,animals were castrated on day one of the study. Treatment with compoundof formula S-II began nine days post ORX and was administered daily viaoral gavage for fourteen days.

The animals were sacrificed under anesthesia (ketamine/xyalzine, 87:13mg/kg) and body weights were recorded. In addition, ventral prostate,seminal vesicles, and levator ani muscle were removed, individuallyweighed, normalized to body weight, and expressed as a percentage ofintact control. Student's T-test was used to compare individual dosegroups to the intact control group. Significance was defined a priori asa P-value<0.05. Ventral prostate and seminal vesicle weights wereevaluated as a measure of androgenic activity, whereas levator animuscle weight was evaluated as a measure of anabolic activity. Blood wascollected from the abdominal aorta, centrifuged, and sera were frozen at−80° C. prior to determination of serum hormone levels. Serumluteinizing hormone (LH) and follicle stimulating hormone (FSH)concentrations were determined.

Results:

A series of dose-response studies in intact and castrated rats in orderto evaluate the potency and efficacy of compound of formula S-II in bothandrogenic (prostate and seminal vesicles) and anabolic (levator animuscle) tissue was conducted. In intact animals, compound of formulaS-II treatment resulted in decreases in the weight of both prostate andseminal vesicles while the levator ani muscle weight was significantlyincreased. Levator ani muscle weight following compound of formula S-IItreatment were 100%±10%, 98%±7%, 110%±5%, 110%±5%, 125%±10%, and129%±10% of intact controls following doses of 0.01, 0.03, 0.1, 0.3,0.75, and 1 mg/day, respectively. The prostate weights were 117%±20%,98%±15%, 82%±20%, 62%±5%, 107%±30%, and 110%±14% of intact controlsfollowing doses of 0.01, 0.03, 0.1, 0.3, 0.75, and 1 mg/day,respectively. These results are significant since current androgentherapies are contraindicated in some patient populations due to theproliferative androgenic effects in prostate and breast tissues.However, many patients in these populations could benefit from theanabolic actions of androgens in muscle and bone. Since compound offormula (S-II) exhibited tissue selective anabolic effects, it may bepossible to treat patient groups in which androgens were contraindicatedin the past.

In castrated, ORX animals, prostate weights following compound offormula S-II treatment were 10%±3%, 12%±3%, 26%±7%, 39%±6%, 60%±14%,88%±16%, and 123%±22% of intact controls following doses of 0, 0.01,0.03, 0.1, 0.3, 0.75, and 1 mg/day, respectively (FIG. 2). Similarly,seminal vesicle weights were 11%±1%, 11%±1%, 11%±1%, 27%±14%, 58%±18%,86%±12%, and 100%±8% of intact controls following doses of 0, 0.01,0.03, 0.1, 0.3, 0.75, and 1 mg/day, respectively (FIG. 2). Significantincreases were seen in levator ani muscle weights in all dose groups,when compared to intact controls. The levator ani muscle weights were48%±8%, 50%±5%, 62%±6%, 89%±10%, 118%±6%, 134%±8% and 129%±14% of intactcontrols corresponding to 0, 0.01, 0.03, 0.1, 0.3, 0.75, and 1.0 mg/daydose groups, respectively (FIG. 2).

Testosterone propionate (TP) andS-3-(4-acetylaminophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)propionamide (S-4), maximally stimulated the levator ani muscle weightto 104% and 101%, respectively. These data show that compound of formulaS-II exhibited significantly greater efficacy and potency than either TPor S-4. As a whole, these data show that compound of formula S-II isable to stimulate muscle growth in the presence or absence oftestosterone while exerting anti-proliferative effects on the prostate.These data show that that compound of formula S-II restores lost musclemass in patients with sarcopenia or cachexia. Additionally, theantiproliferative effects of compound of formula S-II on the prostatemay allow some patient populations, in which androgens are currentlycontraindicated, access to anabolic agents.

Compound of formula S-II exhibited anabolic muscle/prostate ratio incastrated rats of 4.10, 2.39, 2.28, 1.97, 1.53, 1.05 following doses of0.01, 0.03, 0.1, 0.3, 0.75 and 1 mg/day, respectively.

Pharmacology results following 1 mg/day of compound of formula S-IIexhibited that prostate weight was 110%±14% of intact control andlevator ani muscle weight was 129%±10% of intact control. Compound offormula S-II maintained prostate weight following orchidectomy at123±22% of intact controls and levator ani muscle weight at 129±14% ofintact controls. A range of between 0.1 mg/day to 0.3 mg/day of compoundof formula S-II restored 100% of levator ani muscle weight, whilebetween 39 to 60% prostate weight was restored.

Example 5 In Vitro CYP Inhibition Assay

Materials and Methods:

P450 enzyme inhibition was measured using human cDNA-expressed CYP3A4,2D6, 2C19, 2C9, and 1A2 recombinant enzymes and fluorogenic substrates(coumarin analogues) that are converted to fluorescent products. Theanalogues utilized for each isoenzyme are as follows:7-benzyloxy-trifluoromethylcoumarin, (BFC) for 3A4;3-[2-(N,N-diethyl-N-methyl amino)ethyl]7-methoxy-4-methylcoumarin,(AMMC) for 2D6; 3-cyano-7-ethoxycoumarin, (CEC) for 2C19 and 1 A2; and7-methoxy-4-trifluoro-methylcoumarin, (MFC) for 2C9. These substrateswere utilized at a single concentration (either 50 μM or 75 μM) at ornear the apparent K_(m) for each substrate. Fluorescence intensity wasmeasured using a Wallac 1420 Victor³ Multi-label Counter Model(PerkinElmer, Wellesley, Mass.), with an excitation wavelength filter of405 nm, and an emission filter of 460 nm (535 nm for the 3A4 and 2C9substrates). Compound stocks (10 mM in a 4:1 ratio of acetonitrile:DMSO)were tested in this study using an 8-point dose response curve induplicate (ranging from 0.15 μM-20.0 μM). The concentration ofacetonitrile was kept constant at 0.4%, and the reaction was carried outat 37° C. for 30 minutes. Averages (minus background) and IC₅₀ valueswere calculated.

Results:

The in vitro screening results for potential drug-drug interactions(DDI) of SARM compound of formula S-II is presented in Table 2:

TABLE 2 CYP (P450) Inhibition, IC₅₀ (μM) Compound 3A4 2D6 2C19 2C9 1A2S-II >20 17.7 2.4 1.3 >20

Example 6 Pharmacokinetics of Compound of Formula (S-II) in Dogs

In order to determine the pharmacokinetics of compound of formula S-II,the is compound was administered to beagle dogs perorally, andcirculating plasma levels, terminal elimination half-life (t_(1/2)),total body clearance (CL), terminal volume distribution (Vz) andabsolute bioavailability (F %) (Table 3) were determined. Table 3:

Compound S-II T_(1/2) (hr) 37 ± 26.8 CL (mL/min/kg) 0.36 ± 0.12   Vz(mL/kg) 1266 ± 352   F % 72.5%

Example 7 Anabolic and Androgenic Activity of SARM Compounds in Intactand Castrated Male Rats

The in vivo pharmacological activity of each synthetic AR ligand (listedin Table 4, below) was examined in five male Sprague-Dawley ratsweighing approximately 200 g. Animals were castrated via a scrotalincision under anesthesia 24 h before drug treatments and received dailysc injections of the compound of interest at a dose rate of 1 mg/d for14 d. All compounds of interest were freshly dissolved in vehiclecontaining dimethylsulfoxide (5%, vol/vol) in polyethylene glycol 300before dose administration. An additional two groups of animals with orwithout castration received vehicle only and served as castrated orintact control groups, respectively. Animals were killed at the end ofthe treatment. Plasma samples were collected and stored at −80° C. forfuture use. The ventral prostate, seminal vesicles, and levator animuscle were removed, cleared of extraneous tissue, and weighed. Allorgan weights were normalized to body weight and compared. The weightsof prostate and seminal vesicles were used to evaluate androgenicactivity, whereas the levator ani muscle weight was used as a measure ofanabolic activity. Ventral prostate weights in SARM treated castratedrats were all (except C-6) statistically lowered than intact control(FIG. 4). Whereas levator ani weights in SARM castrated rats treatedwith C-3, C-6, C-8, C-10, C-11, or C-18 demonstrated support of muscleweight same as or in excess of intact control (FIG. 3). Further S-1,C-1, C-4, C-22, and C-23 demonstrated levator ani agonism of >75% ofintact control (FIG. 3) vs. <25% of intact control in all of these casesfor ventral prostate (FIG. 4). This demonstrated tissue-selectiveanabolism for a variety of SARMs of this invention. The results aregraphically depicted in FIGS. 3 and 4.

TABLE 4

Compound R₁ R₂ R₃ R₄ R₅ S-1  H H F H H C-1  F H F H H C-2  CH₃ H F H HC-3  H F F H H C-4  H Cl F H H C-6  H F Cl H H C-8  F H Cl H H C-10 H ClCl H H C-11 H F NO₂ H H C-12 F H NO₂ H H C-13 F F F H H C-14 F F H F HC-17 F H F H F C-18 F H F F H C-22 Cl H Cl Cl H C-23 F F F F F

Example 8 Effects of SARM Compounds on Growth Performance and CarcassComposition of Finishing Pigs

Materials and Methods:

The effects of SARM as represented by compound of formula S-II on growthperformance and carcass composition of finishing pigs was examined.Forty crossbred barrows, (TR4×C22) with an initial weight of 209.4 lbwere used for this 28-d experiment. Pigs were blocked by weight andallotted to one of four treatments with ten replicate pens pertreatment. Pigs were housed with one pig per pen in an environmentallycontrolled finishing barn with 4 ft×4 ft slatted pens.

All animals were fed a corn-soybean meal diet with 1% corn oil. For theis treated groups, appropriate quantities of a compound of formula S-II(referred to as SARM in the text and figures/tables of this example)were dissolved in 100 mL of polysorbate (tween) 80 and diluted with 20lbs of corn oil prior to incorporation into the test diet. Final SARMconcentrations were 1, 3, and 10 ppm. All animals were fed theirrespective diets for the duration of the study. The test diets contained1.07% TID lysine. Prior to being placed on study, all pigs were fed acommon corn-soybean meal diet formulated to 0.75% TID lysine.

Pigs were allowed ad libitum access to feed and water. Pigs and feederswere weighed on day 7, 14, 21, and 28 to calculate average daily gain(ADG), average daily feed intake (ADFI), and feed-to-gain ratio (F/G orF:G). Each pen served as an experimental unit for all statisticalanalysis.

Pigs were slaughtered at the Kansas State University Meats Laboratory atthe end of the study for collection of individual carcass data. At 24hours postmortem, the right side of the carcass was frozen at −40° C.for approximately 1 h. After freezing, sides were ground once through agrinder equipped with a 19 mm die, then mixed and ground through asecond grinder equipped with a 9.5 mm die. A sub sample of groundcarcass was then chemically analyzed to determine percentages of crudeprotein, moisture/dry matter, lipid, and ash. Carcass measurements weredone on the left side of the carcass, and a sample of lean and fat wastaken from the longissimus at approximately the 10^(th) rib.

The data were analyzed as a randomized complete-block design. Analysisof variance was performed by using the MIXED procedure of SAS. Linearand quadratic contrasts were used to evaluate the effects of increasingthe level of the SARM on growth and carcass performance.

Results:

Although there were few statistical differences observed in the measuredparameters due to the small group sizes and individual housing ofexperimental animals, we observed positive trends in several keyparameters as shown in FIG. 5. Raw data are also summarized below. SARMincreased average daily gain (ADG) over the course of the study (FIG.5A), decreased feed to gain ratio (F:G) (FIG. 5B), increased fat freelean gain per day (FIG. 5C), and dramatically increased ADG for days21-28 (FIG. 5D).

Further, SARM treatment resulted in significantly increased Day 0-7 F:Gand decreased Day 8-14 average daily feed intake (ADFI). Table 5 showsthe weekly as well as the overall ADG, ADFI, and F:G data from thestudy.

TABLE 5 Param- Vehicle SARM, ppm Probability, P< eter Control 1 3 10Linear Quadratic Day 0-7 ADG 2.51 2.89 2.37 2.17 0.07 0.87 ADFI 7.667.56 7.54 7.4 0.37 0.8 F:G 3.24 2.67 3.27 3.85 0.05 0.62 Day 8-14 ADG2.74 2.59 2.65 2.37 0.14 0.94 ADFI 8.55 8.74 8.5 7.89 0.04 0.67 F:G 3.543.52 3.3 3.46 0.83 0.57 Day 15-21 ADG 2.25 2.33 2.65 2.43 0.39 0.21 ADFI7.99 8.33 8.61 7.78 0.45 0.09 F:G 3.7 3.88 3.4 3.33 0.19 0.71 Day 22-28ADG 2.77 3.15 3.15 3.03 0.92 0.19 ADFI 8.19 8.51 8.89 8.33 0.79 0.26 F:G3.12 2.72 2.87 2.83 0.95 0.24 Day 0-28 ADG 2.57 2.74 2.7 2.5 0.28 0.31ADFI 8.1 8.28 8.38 7.85 0.29 0.27 F:G 3.2 3.04 3.11 3.17 0.56 0.45

At the time of sacrifice, a carcass composition analysis was performed.The data from this analysis are presented in Table 6. Trends towardsincreased lean mass and decreased fat were obeserved. SARM-treated pigsshowed a 7 to 10% decrease in first rib fat, 3 to 8% decrease in lastrib fat, 2 to 11% decrease in last lumbar fat, 6 to 14% decrease in10^(th) rib fat, and up to a 4% increase in loin eye area (LEA). Treatedanimals also demonstrated up to a 2% improvement in lean percent andpounds of fat free lean. However, due to the variability in this study,none of these measurements reached significance.

TABLE 6 Probability, P< Vehicle SARM, ppm Qua- Parameter Control 1 3 10Linear dratic Heart Wt, lb 0.99 1.04 1.07 1.01 0.92 0.08 Liver Wt, lb4.19 4.58 4.95 4.84 0.05 0.02 Kidney Wt, lb 1.08 1.2 1.18 1.16 0.38 0.3Dress, % 70.3 69.6 69.3 70 0.52 0.23 1^(st) rib fat, in 1.59 1.47 1.481.43 0.21 0.31 Last rib fat, in 0.94 0.9 0.91 0.86 0.57 0.79 in 0.840.77 0.82 0.74 0.16 0.75 10^(th) rib fat, in 0.86 0.78 0.8 0.74 0.35 0.7LEA, in² 7.27 7.26 7.22 7.59 0.09 0.41 Lean, % 52.4 53.2 52.9 54.3 0.161 Fat free lean, lb 104.2 106.9 105.5 106.7 0.46 0.79 ^(a) A total of 40barrows were used (carcass weight of 199 lb)

Table 7 shows the complete data set for all parameters which werecollected in this Example.

TABLE 7 SARM SARM SARM Control (1 PPM) (3 PPM) (10 PPM) ADG (Days 0-7)2.51 2.89 2.37 2.17 ADG (Days 8-14) 2.74 2.59 2.65 2.37 ADG (Days 15-21)2.25 2.33 2.65 2.43 ADG (Days 22-28) 2.77 3.15 3.15 3.03 ADG Total 2.572.74 2.70 2.50 ADFI (Days 0-7) 7.66 7.56 7.54 7.40 ADFI (Days 8-14) 8.558.74 8.50 7.89 ADFI (Days 15-21) 7.99 8.33 8.61 7.78 ADFI (Days 22-28)8.19 8.51 8.89 8.33 F/G (Days 0-7) 3.24 2.67 3.27 3.85 F/G (Days 8-14)3.54 3.52 3.30 3.46 F/G (Days 15-21) 3.70 3.88 3.40 3.33 F/G (Days22-28) 3.12 2.72 2.87 2.83 F/G Total 3.20 3.04 3.11 3.17 Gain (Days 0-7)17.5 20.3 16.6 15.2 Gain (Days 8-14) 19.2 18.2 18.6 16.6 Gain (Days15-21) 15.7 16.3 18.5 17.0 Gain (Days 22-28) 19.4 22.0 22.0 21.2 InitialWt 209 209 209 209 Live Wt 284 289 288 281 L side 97.6 98.0 97.7 96.8 Rside 101 103 102 99.8 Carcass Wt 199 201 200 197 Dress % 70% 70% 69% 70%1st rib fat 1.59 1.47 1.48 1.43 Last rib fat 0.935 0.900 0.905 0.855Last lumbar fat 0.835 0.770 0.815 0.740 10th rib fat 0.855 0.780 0.8000.735 LEA 7.27 7.26 7.22 7.59 lb FFL 104 107 106 107 lbs FFL/D 0.7270.822 0.774 0.814 Heart Wt 0.988 1.04 1.07 1.01 Liver Wt 4.19 4.58 4.954.84 Kidney Wt 1.08 1.20 1.18 1.16

The potential for using SARM (compound of formula S-II) to improvefinishing characteristics in food-animals was demonstrated. Feeding theSARM greatly improved ADG and F:G while reducing carcass crude fat. Someof the greatest improvements in these parameters were noted as thelowest dose (1 ppm). Lesser effects at high dose have been observed withother SARMs. Taken as a whole, these data support that SARM treatmentwould improve carcass composition and growth performance which are keyfactors in the economics of swine production.

Example 9 Effects of SARM Compounds on Growth Performance and CarcassComposition of Finishing Pigs Compared with Paylean®

Further studies with lower doses, larger group sizes and a directcomparison to ractopamine are conducted. As a direct competitor toractopamine, the SARM treated animals demonstrate the highest ADGs inthe fourth week of treatment. By the fourth week of treatment withractopamine the animals are desensitized to the beta-agonist and theproducers are seeing diminished returns in lean mass gain. Therefore,longer treatment periods (>28 days) may be advantageous to the producerswhen feeding a SARM than when feeding ractopamine.

Example 10 Synthesis of Compound of Formula S-XXIII Synthesis of (S)Enantiomer of Compound of Formula XXIII (FIG. 6)

(2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid

D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH andcooled in an ice bath; the resulting alkaline solution was diluted withacetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride(13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneouslyadded over 40 min to the aqueous solution of D-proline in an ice bath.The pH of the mixture was kept at 10-11° C. during the addition of themethacryloyl chloride. After stirring (3 h, room temperature), themixture was evaporated in vacuo at a temperature at 35-45° C. to removeacetone. The resulting solution was washed with ethyl ether and wasacidified to pH 2 with concentrated HCl. The acidic mixture wassaturated with NaCl and was extracted with EtOAc (100 mL×3). Thecombined extracts were dried over Na₂SO₄, filtered through Celite, andevaporated in vacuo to give the crude product as a colorless oil.Recrystallization of the oil from ethyl ether and hexanes afforded 16.2g (68%) of the desired compound as colorless crystals: mp 102-103° C.(lit. [214] mp 102.5-103.5° C.); the NMR spectrum of this compounddemonstrated the existence of two rotamers of the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15(s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers,vinyl CH₂), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for thesecond rotamer (totally 1H for both rotamers, CH at the chiral center),3.57-3.38 (m, 2H, CH₂), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH₂, CH,Me); ¹³C NMR (75 MHz, DMSO-d₆) δ for major rotamer 173.3, 169.1, 140.9,116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0,141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737(C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm⁻¹; [α]_(D)²⁶+80.8° (c=1, MeOH); Anal. Calcd. for C₉H₁₃NO₃: C, 59.00; H, 7.15; N,7.65. Found: C, 59.13; H, 7.19; N, 7.61.

(3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-dione

A solution of NBS (23.5 g, 0.132 mol) in 100 mL of DMF was addeddropwise to a stirred solution of the (methyl-acryloyl)-pyrrolidine(16.1 g, 88 mmol) in 70 mL of DMF under argon at room temperature, andthe resulting mixture was stirred 3 days. The solvent was removed invacuo, and a yellow solid was precipitated. The solid was suspended inwater, stirred overnight at room temperature, filtered, and dried togive 18.6 g (81%) (smaller weight when dried ˜34%) of the title compoundas a yellow solid: mp 152-154° C. (lit. [214] mp 107-109° C. for theS-isomer); ¹H NMR (300 MHz, DMSO-d₆) δ 4.69 (dd, J=9.6 Hz, J=6.7 Hz, 1H,CH at the chiral center), 4.02 (d, J=11.4 Hz, 1H, CHH_(a)), 3.86 (d,J=11.4 Hz, 1H, CHH_(b)), 3.53-3.24 (m, 4H, CH₂), 2.30-2.20 (m, 1H, CH),2.04-1.72 (m, 3H, CH₂ and CH), 1.56 (s, 2H, Me); ¹³C NMR (75 MHz,DMSO-d₆) δ 167.3, 163.1, 83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR(KBr) 3474, 1745 (C═O), 1687 (C═O), 1448, 1377, 1360, 1308, 1227, 1159,1062 cm⁻¹; [α]D²⁶+124.5° (c=1.3, chloroform); Anal. Calcd. forC₉H₁₂BrNO₃: C, 41.24; H, 4.61; N, 5.34. Found: C, 41.46; H, 4.64; N,5.32.

(2R)-3-Bromo-2-hydroxy-2-methylpropanoic Acid

A mixture of bromolactone (18.5 g, 71 mmol) in 300 mL of 24% HBr washeated at reflux for 1 h. The resulting solution was diluted with brine(200 mL), and was extracted with ethyl acetate (100 mL×4). The combinedextracts were washed with saturated NaHCO₃ (100 mL×4). The aqueoussolution was acidified with concentrated HCl to pH=1, which, in turn,was extracted with ethyl acetate (100 mL×4). The combined organicsolution was dried over Na₂SO₄, filtered through Celite, and evaporatedin vacuo to dryness. Recrystallization from toluene afforded 10.2 g(86%) of the desired compound as colorless crystals: mp 107-109° C.(lit. [214] mp 109-113° C. for the S-isomer); ¹H NMR (300 MHz, DMSO-d₆)δ 3.63 (d, J=10.1 Hz, 1H, CHH_(a)), 3.52 (d, J=10.1 Hz, 1H, CHH_(b)),1.35 (s, 3H, Me); IR (KBr) 3434 (OH), 3300-2500 (COOH), 1730 (C═O),1449, 1421, 1380, 1292, 1193, 1085 cm⁻¹; [α]_(D) ²⁶+10.5° (c=2.6, MeOH);Anal. Calcd. for C₄H₇BrO₃: C, 26.25; H, 3.86. Found: C, 26.28; H, 3.75.

Synthesis of(2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide

Thionyl chloride (46.02 g, 0.39 mol) was added dropwise to a cooledsolution (less than 4° C.) of R-18 (51.13 g, 0.28 mol) in 300 mL of THFunder an argon atmosphere. The resulting mixture was stirred for 3 hunder the same condition. To this was added Et₃N (39.14 g, 0.39 mol) andstirred for 20 min under the same condition. After 20 min,5-amino-2-cyanobenzotrifluoride (40.0 g, 0.21 mol), 400 mL of THF wereadded and then the mixture was allowed to stir overnight at roomtemperature. The solvent was removed under reduced pressure to give asolid which was treated with 300 mL of H₂O, extracted with EtOAc (2×400mL). The combined organic extracts were washed with saturated NaHCO₃solution (2×300 mL) and brine (300 mL). The organic layer was dried overMgSO₄ and concentrated under reduced pressure to give a solid which waspurified from column chromatography using CH₂Cl₂/EtOAc (80:20) to give asolid. This solid was recrystallized from CH₂Cl₂/hexane to give 55.8 g(73.9%) of(2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide(R-19) as a light-yellow solid.

¹H NMR (CDCl₃/TMS) δ 1.66 (s, 3H, CH₃), 3.11 (s, 1H, OH), 3.63 (d,J=10.8 Hz, 1H, CH₂), 4.05 (d, J=10.8 Hz, 1H, CH₂), 7.85 (d, J=8.4 Hz,1H, ArH), 7.99 (dd, J=2.1, 8.4 Hz, 1H, ArH), 8.12 (d, J=2.1 Hz, 1H,ArH), 9.04 (bs, 1H, NH). Calculated Mass: 349.99, [M-H]⁻ 349.0. M.p.:124-126° C.

Synthesis of(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpropanamide

A mixture of bromoamide((2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide,R-19 (2.0 g, 5.70 mmol) and anhydrous K₂CO₃ (2.4 g, 17.1 mmol) in 50 mLof acetone was heated to reflux for 2 h and then concentrated underreduced pressure to give a solid. The resulting solid was treated with2-fluoro-4-hydroxybenzonitrile (1.2 g, 8.5 mmol) and anhydrous K₂CO₃(1.6 g, 11.4 mmol) in 50 mL of 2-propanol and was heated to reflux for 3h, then concentrated under reduced pressure to give a solid. The residuewas was treated with 100 mL of H₂O and then extracted with EtOAc (2×100mL). The combined EtOAc extracts were washed with 10% NaOH (4×100 mL)and brine, successively. The organic layer was dried over MgSO₄ and thenconcentrated under reduced pressure to give an oil which wascrystallized from CH₂Cl₂/hexane to give 0.5 g (23%) of(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpropanamideas a colorless solid.

¹H NMR (CDCl₃/TMS) δ 1.63 (s, 3H, CH₃), 3.34 (bs, 1H₂OH), 4.08 (d,J=9.17 Hz, 1H, CH), 4.50 (d, J=9.17 Hz, 1H, CH), 6.74-6.82 (m, 2H, ArH),7.50-7.55 (m, 1H, ArH), 7.81 (d, J=8.50 Hz, 1H, ArH), 7.97 (q, J=2.03,8.50 Hz, 1H, ArH), 8.11 (d, J=2.03 Hz, 1H, ArH), 9.12 (s, 1H, NH).Calculated Mass: 407.1, [M+Na]⁺430.0.

Mp: 124-125° C.

FIG. 6 schematically depicts some embodiments of synthetic processes toobtain compound of formula S-XXIII.

Example 11 Preclinical Anabolic and Androgenic Pharmacology of Compoundfor Formula (S-XXIII) in Intact and Castrate Male Rats

Anabolic and androgenic efficacy of compound of formula S-XXIIIadministered by daily oral gavage were tested. The S-isomer of compound(XXIII) was synthesized and tested as described herein.

Materials and Methods:

Male Sprague-Dawley rats weighing approximately 200 g were purchasedfrom Harlan Bioproducts for Science (Indianapolis, Ind.). The animalswere maintained on a 12-h light/dark cycle with food (7012C LM-485Mouse/Rat Sterilizable Diet, Harlan Teklad, Madison, Wis.) and wateravailable ad libitum. The animal protocol was reviewed and approved bythe Institutional Animal Care and Use Committee of the University ofTennessee.

The test article for this study was weighed and dissolved in 10% DMSO(Fisher) diluted with PEG 300 (Acros Organics, N.J.) for preparation ofthe appropriate dosage concentrations. The animals were housed in groupsof 2 to 3 animals per cage. Animals were randomly assigned to one ofseven groups consisting of 4 to 5 animals per group. Control groups(intact and ORX) were administered vehicle daily. Compound of formulaS-XXIII was administered via oral gavage at doses of 0.01, 0.03, 0.1,0.3, 0.75, and 1 mg/day to both intact and ORX groups. Whereappropriate, animals were castrated on day one of the study. Treatmentwith compound of formula S-XXIII began nine days post ORX and wasadministered daily via oral gavage for fourteen days.

The animals were sacrificed under anesthesia (ketamine/xyalzine, 87:13mg/kg) and body weights were recorded. In addition, ventral prostate,seminal vesicles, and levator ani muscle were removed, individuallyweighed, normalized to body weight, and expressed as a percentage ofintact control. Student's T-test was used to compare individual dosegroups to the intact control group. Significance was defined a priori asa P-value<0.05. Ventral prostate and seminal vesicle weights wereevaluated as a measure of androgenic activity, whereas levator animuscle weight was evaluated as a measure of anabolic activity. Blood wascollected from the abdominal aorta, centrifuged, and sera were frozen at−80° C. prior to determination of serum hormone levels. Serumluteinizing hormone (LH) and follicle stimulating hormone (FSH)concentrations were determined.

Results:

A series of dose-response studies in intact and castrated rats in orderto evaluate the potency and efficacy of compound of formula S-XXIII inboth androgenic (prostate and seminal vesicles) and anabolic (levatorani muscle) tissue was conducted. In intact animals, compound of formulaS-XXIII treatment resulted in decreases in the weight of both prostateand seminal vesicles while the levator ani muscle weight wassignificantly increased. Levator ani muscle weight following compound offormula S-XXIII treatment were 116%±7%, 134%±8%, 134%±21%, 134%±11%,142%±10%, and 147%±10% of intact controls, following treatment with0.01, 0.03, 0.1, 0.3, 0.75, and 1.0 mg/day dose groups, respectively.The prostate weights were 98%±21%, 99%±8%, 85%±18%, 98%±22%, 126%±17%,and 126%±17% of intact controls, following treatment with 0.01, 0.03,0.1, 0.3, 0.75, and 1 mg/day, respectively. Similarly seminal vesicleweight was 115%±12%, 109%±17%, 106%±13%, 121%±11%, 157%±5%, and 136%±3%of intact controls following treatment with 0.01, 0.03, 0.1, 0.3, 0.75,and 1 mg/day, respectively. The results are graphically presented inFIG. 7. These results are significant since current androgen therapiesare contraindicated in some patient populations due to the proliferativeandrogenic effects in prostate and breast tissues. However, manypatients in these populations could benefit from the anabolic actions ofandrogens in muscle and bone. Since compound of formula S-XXIIIexhibited tissue selective anabolic effects, it may be possible to treatpatient groups in which androgens were contraindicated in the past.

In castrated (ORX) animals, prostate weights following compound offormula S-XXIII treatment were 24%±4%, 37%±9%, 50%±11%, 88%±16%,132%±16%, and 118±12% of intact controls following doses of 0, 0.01,0.03, 0.1, 0.3, 0.75, and 1 mg/day, respectively. Similarly, seminalvesicle weights were 15%±2%, 25%±9%, 67%±20%, 113%±6%, 155%±16%, and160%±7% of intact controls, following doses of 0, 0.01, 0.03, 0.1, 0.3,0.75, and 1 mg/day, respectively. Significant increases were seen inlevator ani muscle weights of in all dose groups, when compared tointact controls. The levator ani muscle weights were 71%±4%, 101%±15%,125%±20%, 126%±14%, 151±9%, and 143±17% of intact controls correspondingto 0, 0.01, 0.03, 0.1, 0.3, 0.75, and 1.0 mg/day dose groups,respectively. The results are graphically presented in FIG. 8.

One unexpected finding was that administration of only 0.03 mg/day wasable to fully restore levator ani muscle weight.

Comparable administration of testosterone propionate (TP) andS-3-(4-acetylaminophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)propionamide, maximally stimulated the levator ani muscle weight to 104%and 101%, respectively, indicating the significantly enhanced efficacyand potency of compound of formula S-XXIII. Taken together, these datashow that compound of formula S-XXIII restores lost muscle mass, whichin some embodiments, finds valuable application in patients withsarcopenia or cachexia, or other wasting diseases or disorders.Additionally, the antiproliferative effects of compound of formulaS-XXIII on the prostate may allow some patient populations, in whichandrogens are currently contraindicated, access to anabolic agents. Emaxvalues were obtained and were 147%±10%, 188%±135%, and 147%±10% forprostate, seminal vesicles, and levator ani, respectively. The ED₅₀ inprostate, seminal vesicles, and levator ani was 0.21±0.04, 0.2±0.04, and0.03±0.01 mg/day, respectively. These results are graphically depictedin FIG. 9.

Example 12 Synthesis of Compound XXIV Synthesis of (S) Enantiomer ofCompound of Formula (XXIV) (FIG. 10)

(2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid

D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH andcooled in an ice bath; the resulting alkaline solution was diluted withacetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride(13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneouslyadded over 40 min to the aqueous solution of D-proline in an ice bath.The pH of the mixture was kept at 10-11° C. during the addition of themethacryloyl chloride. After stirring (3 h, room temperature), themixture was evaporated in vacuo at a temperature at 35-45° C. to removeacetone. The resulting solution was washed with ethyl ether and wasacidified to pH 2 with concentrated HCl. The acidic mixture wassaturated with NaCl and was extracted with EtOAc (100 mL×3). Thecombined extracts were dried over Na₂SO₄, filtered through Celite, andevaporated in vacuo to give the crude product as a colorless oil.Recrystallization of the oil from ethyl ether and hexanes afforded 16.2(68%) of the desired compound as colorless crystals: mp 102-103° C.(lit. [214] mp 102.5-103.5° C.); the NMR spectrum of this compounddemonstrated the existence of two rotamers of the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15(s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers,vinyl CH₂), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for thesecond rotamer (totally 1H for both rotamers, CH at the chiral canter),3.57-3.38 (m, 2H, CH₂), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH₂, CH,Me); ¹³C NMR (75 MHz, DMSO-d₆) δ for major rotamer 173.3, 169.1, 140.9,116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0,141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737(C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm⁻¹; [α]_(D)²⁶+80.8° (c=1, MeOH); Anal. Calcd. for C₉H₁₃NO₃: C, 59.00; H, 7.15; N,7.65. Found: C, 59.13; H, 7.19; N, 7.61.

(3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-dione

A solution of NBS (23.5 g, 0.132 mol) in 100 mL of DMF was addeddropwise to a stirred solution of the (methyl-acryloyl)-pyrrolidine(16.1 g, 88 mmol) in 70 mL of DMF under argon at room temperature, andthe resulting mixture was stirred 3 days. The solvent was removed invacuo, and a yellow solid was precipitated. The solid was suspended inwater, stirred overnight at room temperature, filtered, and dried togive 18.6 g (81%) (smaller weight when dried ˜34%) of the title compoundas a yellow solid: mp 152-154° C. (lit. [214] mp 107-109° C. for theS-isomer); ¹H NMR (300 MHz, DMSO-d₆) δ 4.69 (dd, J=9.6 Hz, J=6.7 Hz, 1H,CH at the chiral center), 4.02 (d, J=11.4 Hz, 1H, CHH_(a)), 3.86 (d,J=11.4 Hz, 1H, CHH_(b)), 3.53-3.24 (m, 4H, CH₂), 2.30-2.20 (m, 1H, CH),2.04-1.72 (m, 3H, CH₂ and CH), 1.56 (s, 2H, Me); ¹³C NMR (75 MHz,DMSO-d₆) δ 167.3, 163.1, 83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR(KBr) 3474, 1745 (C═O), 1687 (C═O), 1448, 1377, 1360, 1308, 1227, 1159,1062 cm⁻¹; [α]_(D) ²⁶+124.5° (c=1.3, chloroform); Anal. Calcd. forC₉H₁₂BrNO₃: C, 41.24; H, 4.61; N, 5.34. Found: C, 41.46; H, 4.64; N,5.32.

(2R)-3-Bromo-2-hydroxy-2-methylpropanoic Acid

A mixture of bromolactone (18.5 g, 71 mmol) in 300 mL of 24% HBr washeated at reflux for 1 h. The resulting solution was diluted with brine(200 mL), and was extracted with ethyl acetate (100 mL×4). The combinedextracts were washed with saturated NaHCO₃ (100 mL×4). The aqueoussolution was acidified with concentrated HCl to pH=1, which, in turn,was extracted with ethyl acetate (100 mL×4). The combined organicsolution was dried over Na₂SO₄, filtered through Celite, and evaporatedin vacuo to dryness. Recrystallization from toluene afforded 10.2 g(86%) of the desired compound as colorless crystals: mp 107-109° C.(lit. [214] mp 109-113° C. for the S-isomer); ¹H NMR (300 MHz, DMSO-d₆)δ 3.63 (d, J=10.1 Hz, 1H, CHH_(a)), 3.52 (d, J=10.1 Hz, 1H, CHH_(b)),1.35 (s, 3H, Me); IR (KBr) 3434 (OH), 3300-2500 (COOH), 1730 (C═O),1449, 1421, 1380, 1292, 1193, 1085 cm⁻¹; [α]_(D) ²⁶+10.5° (c=2.6, MeOH);Anal. Calcd. for C₄H₇BrO₃: C, 26.25; H, 3.86. Found: C, 26.28; H, 3.75.

Synthesis of(2R)-3-bromo-N-(3-chloro-4-cyanophenyl)-2-hydroxy-2-methylpropanamide

Thionyl chloride (7.8 g, 65.5 mmol) was added dropwise to a cooledsolution (less than 4° C.) of (R)-3-bromo-2-hydroxy-2-methylpropanoicacid (9.0 g, 49.2 mol) in 50 mL of THF under an argon atmosphere. Theresulting mixture was stirred for 3 h under the same condition. To thiswas added Et₃N (6.6 g, 65.5 mol) and stirred for 20 min under the samecondition. After 20 min, 4-amino-2-chlorobenzonitrile (5.0 g, 32.8 mmol)and 100 mL of THF were added and then the mixture was allowed to stirovernight at room temperature. The solvent was removed under reducedpressure to give a solid which was treated with 100 mL of H₂O, extractedwith EtOAc (2×150 mL). The combined organic extracts were washed withsaturated NaHCO₃ solution (2×100 mL) and brine (300 mL), successively.The organic layer was dried over MgSO₄ and concentrated under reducedpressure to give a solid which was purified from column chromatographyusing EtOAc/hexane (50:50) to give 7.7 g (49.4%) of target compound as abrown solid.

¹H NMR (CDCl₃/TMS) δ 1.7 (s, 3H, CH₃), 3.0 (s, 1H, OH), 3.7 (d, 1H, CH),4.0 (d, 1H, CH), 7.5 (d, 1H, ArH), 7.7 (d, 1H, ArH), 8.0 (s, 1H, ArH),8.8 (s, 1H, NH). MS: 342.1 (M+23). Mp 129° C.

Synthesis of(S)—N-(3-chloro-4-cyanophenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide

A mixture of bromoamide (2.0 g, 6.3 mmol), anhydrous K₂CO₃ (2.6 g, 18.9mmol) in 50 mL of acetone was heated to reflux for 2 h and thenconcentrated under reduced pressure to give a solid. The resulting solidwas treated with 4-cyanophenol (1.1 g, 9.5 mmol) and anhydrous K₂CO₃(1.7 g, 12.6 mmol) in 50 mL of 2-propanol was heated to reflux for 3 hand then concentrated under reduced pressure to give a solid. Theresidue was treated with 100 mL of H₂O and then extracted with EtOAc(2×100 mL). The combined EtOAc extracts were washed with 10% NaOH (4×100mL) and brine, successively. The organic layer was dried over MgSO₄ andthen concentrated under reduced pressure to give an oil which waspurified by column chromatography using EtOAc/hexane (50:50) to give asolid. The solid was recrystallized from CH₂Cl₂/hexane to give 1.4 g(61.6%) of(S)—N-(3-chloro-4-cyanophenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideas a colorless solid.

¹H NMR (CDCl₃/TMS) δ 1.61 (s, 3H, CH₃), 3.25 (s, 1H₂OH), 4.06 (d, J=9.15Hz, 1H, CH), 4.50 (d, J=9.15 Hz, 1H, CH), 6.97-6.99 (m, 2H, ArH),7.53-7.59 (m, 4H, ArH), 7.97 (d, J=2.01 Hz, 1H, ArH), 8.96 (s, 1H, NH).Calculated Mass: 355.1, [M+Na]⁺378.0. Mp: 103-105° C.

Example 13 Preclinical Anabolic and Androgenic Pharmacology of S-XXIV inIntact and Castrate Male Rats

Anabolic and androgenic efficacy of compound of formula S-XXIVadministered by daily oral gavage were tested. The S-isomer of compoundS-XXIV was synthesized and tested as described herein.

Materials and Methods:

Male Sprague-Dawley rats weighing approximately 200 g were purchasedfrom Harlan Bioproducts for Science (Indianapolis, Ind.). The animalswere maintained on a 12-h light/dark cycle with food (7012C LM-485Mouse/Rat Sterilizable Diet, Harlan Teklad, Madison, Wis.) and wateravailable ad libitum. The animal protocol was reviewed and approved bythe Institutional Animal Care and The anabolic and androgenic activityof compound of formula S-XXIV in intact animals was tested, as well as adose response evaluation in acutely orchidectomized (ORX) animals.Regenerative effects of the compound of formula S-XXIV in chronically (9days) ORX rats was similarly evaluated.

The test article for this study was weighed and dissolved in 10% DMSO(Fisher) diluted with PEG 300 (Acros Organics, N.J.) for preparation ofthe appropriate dosage concentrations. The animals were housed in groupsof 2 to 3 animals per cage. Animals were randomly assigned to one ofseven groups consisting of 4 to 5 animals per group. Control groups(intact and ORX) were administered vehicle daily. Compound of formulaS-XXIV was administered via oral gavage at doses of 0.01, 0.03, 0.1,0.3, 0.75, and 1 mg/day to both intact and ORX groups. Whereappropriate, animals were castrated on day one of the study. Treatmentwith compound of formula S-XXIV began nine days post ORX and wasadministered daily via oral gavage for fourteen days.

The animals were sacrificed under anesthesia (ketamine/xyalzine, 87:13mg/kg) and body weights were recorded. In addition, ventral prostate,seminal vesicles, and levator ani muscle were removed, individuallyweighed, normalized to body weight, and expressed as a percentage ofintact control. Student's T-test was used to compare individual dosegroups to the intact control group. Significance was defined a priori asa P-value<0.05. Ventral prostate and seminal vesicle weights wereevaluated as a measure of androgenic activity, whereas levator animuscle weight was evaluated as a measure of anabolic activity. Blood wascollected from the abdominal aorta, centrifuged, and sera were frozen at−80° C. prior to determination of serum hormone levels. Serumluteinizing hormone (LH) and follicle stimulating hormone (FSH)concentrations were determined.

Results:

A series of dose-response studies in intact and castrated rats in orderto evaluate the potency and efficacy of compound of formula S-XXIV inboth androgenic (prostate and seminal vesicles) and anabolic (levatorani muscle) tissue was conducted. In intact animals, compound of formulaS-XXIV treatment resulted in decreases in the weight of both prostateand seminal vesicles while the levator ani muscle weight wassignificantly increased. Levator ani muscle weight following compound offormula S-XXIV treatment were 107%±5%, 103%±7%, 97%±7%, 103%±5%,118%±7%, and 118%±7% of intact controls following doses of 0.01, 0.03,0.1, 0.3, 0.75, and 1 mg/day, respectively. The prostate weights were103%±10%, 99%±10%, 58%±10%, 58%±15%, 65%±20%, and 77%±23% of intactcontrols following doses of 0.01, 0.03, 0.1, 0.3, 0.75, and 1 mg/day,respectively. These results are significant since current androgentherapies are contraindicated in some patient populations due to theproliferative androgenic effects in prostate and breast tissues.However, many patients in these populations could benefit from theanabolic actions of androgens in muscle and bone. Since compound offormula S-XXIV exhibited tissue selective anabolic effects, it may bepossible to treat patient groups in which androgens were contraindicatedin the past.

In castrated, ORX animals, prostate weights following compound offormula S-XXIV treatment were 12%±2%, 17%±6%, 31%±3%, 43%±15%, 54%±17%,58%±10%, and 73%±12% of intact controls following doses of 0, 0.01,0.03, 0.1, 0.3, 0.75, and 1 mg/day, respectively (FIG. 11). Similarly,seminal vesicle weights were 10%±2%, 10%±3%, 13%±4%, 21%±6%, 43%±8%,51%±9%, and 69%±14% of intact controls following doses of 0, 0.01, 0.03,0.1, 0.3, 0.75, and 1 mg/day, respectively (FIG. 11). Significantincreases were seen in levator ani muscle weights of in all dose groups,when compared to intact controls. The levator ani muscle weights were40%±5%, 52%±8%, 67%±9%, 98%±10%, 103%±12%, 105%±12% and 110%±17% ofintact controls corresponding to 0, 0.01, 0.03, 0.1, 0.3, 0.75, and 1.0mg/day dose groups, respectively (FIG. 11).

Testosterone propionate (TP) andS-3-(4-acetylaminophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)propionamide (S-4), maximally stimulated the levator ani muscle weightto 104% and 101%, respectively. These data show that compound of formulaS-XXIV exhibited significantly greater efficacy and potency than eitherTP or S-4. As a whole, these data show that compound of formula S-XXIVis able to stimulate muscle growth in the presence or absence oftestosterone while exerting anti-proliferative effects on the prostate.These data show that the compound of formula S-XXIV restores lost musclemass in patients with sarcopenia or cachexia. Additionally, theantiproliferative effects of the compound of formula S-XXIV on theprostate may allow some patient populations, in which androgens arecurrently contraindicated, access to anabolic agents.

Anabolic ratios were derived comparing muscle/prostate weight incastrated rats. Values obtained were 3.02, 2.13, 2.27, 1.90, 1.83 and1.51 following doses of 0.01, 0.03, 0.1, 0.3, 0.75 and 1 mg/day,respectively.

Animals receiving 1 mg/day of compound of formula S-XXIV exhibited aprostate weight of 77%±23% and levator ani muscle weight of 118%±7% ofintact control values, respectively. Compound of formula S-XXIVmaintained prostate weight following orchidectomy at 73±12% of intactcontrols and levator ani muscle weight at 110±17% of intact controls. Aderived dose of 0.1 mg/day of compound of formula S-XXIV would restorelevator ani muscle weight to 100%, while such dose would only restore43±15% prostate weight.

Example 14 Synthesis of Compound of Formula S-XXV Synthesis of (S)Enantiomer of Compound of Formula XXV (FIG. 12)

(2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid

D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH andcooled in an ice bath; the resulting alkaline solution was diluted withacetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride(13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneouslyadded over 40 min to the aqueous solution of D-proline in an ice bath.The pH of the mixture was kept at 10-11° C. during the addition of themethacryloyl chloride. After stirring (3 h, room temperature), themixture was evaporated in vacuo at a temperature at 35-45° C. to removeacetone. The resulting solution was washed with ethyl ether and wasacidified to pH 2 with concentrated HCl. The acidic mixture wassaturated with NaCl and was extracted with EtOAc (100 mL×3). Thecombined extracts were dried over Na₂SO₄, filtered through Celite, andevaporated in vacuo to give the crude product as a colorless oil.Recrystallization of the oil from ethyl ether and hexanes afforded 16.2g (68%) of the desired compound as colorless crystals: mp 102-103° C.(lit. [214] mp 102.5-103.5° C.); the NMR spectrum of this compounddemonstrated the existence of two rotamers of the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15(s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers,vinyl CH₂), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for thesecond rotamer (totally 1H for both rotamers, CH at the chiral canter),3.57-3.38 (m, 2H, CH₂), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH₂, CH,Me); ¹³C NMR (75 MHz, DMSO-d₆) δ for major rotamer 173.3, 169.1, 140.9,116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0,141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737(C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm⁻¹; [α]_(D)²⁶+80.8° (c=1, MeOH); Anal. Calcd. for C₉H₁₃NO₃: C, 59.00; H, 7.15; N,7.65.

Found: C, 59.13; H, 7.19; N, 7.61.

(3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-dione

A solution of NBS (23.5 g, 0.132 mol) in 100 mL of DMF was addeddropwise to a stirred solution of the (methyl-acryloyl)-pyrrolidine(16.1 g, 88 mmol) in 70 mL of DMF under argon at room temperature, andthe resulting mixture was stirred 3 days. The solvent was removed invacuo, and a yellow solid was precipitated. The solid was suspended inwater, stirred overnight at room temperature, filtered, and dried togive 18.6 g (81%) (smaller weight when dried ˜34%) of the title compoundas a yellow solid: mp 152-154° C. (lit. [214] mp 107-109° C. for theS-isomer); ¹H NMR (300 MHz, DMSO-d₆) δ 4.69 (dd, J=9.6 Hz, J=6.7 Hz, 1H,CH at the chiral center), 4.02 (d, J=11.4 Hz, 1H, CHH_(a)), 3.86 (d,J=11.4 Hz, 1H, CHH_(b)), 3.53-3.24 (m, 4H, CH₂), 2.30-2.20 (m, 1H, CH),2.04-1.72 (m, 3H, CH₂ and CH), 1.56 (s, 2H, Me); ¹³C NMR (75 MHz,DMSO-d₆) δ 167.3, 163.1, 83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR(KBr) 3474, 1745 (C═O), 1687 (C═O), 1448, 1377, 1360, 1308, 1227, 1159,1062 cm⁻¹; [α]_(D) ²⁶+124.5° (c=1.3, chloroform); Anal. Calcd. forC₉H₁₂BrNO₃: C, 41.24; H, 4.61; N, 5.34. Found: C, 41.46; H, 4.64; N,5.32.

(2R)-3-Bromo-2-hydroxy-2-methylpropanoic Acid

A mixture of bromolactone (18.5 g, 71 mmol) in 300 mL of 24% HBr washeated at reflux for 1 h. The resulting solution was diluted with brine(200 mL), and was extracted with ethyl acetate (100 mL×4). The combinedextracts were washed with saturated NaHCO₃ (100 mL×4). The aqueoussolution was acidified with concentrated HCl to pH=1, which, in turn,was extracted with ethyl acetate (100 mL×4). The combined organicsolution was dried over Na₂SO₄, filtered through Celite, and evaporatedin vacuo to dryness. Recrystallization from toluene afforded 10.2 g(86%) of the desired compound as colorless crystals: mp 107-109° C.(lit. [214] mp 109-113° C. for the S-isomer); ¹H NMR (300 MHz, DMSO-d₆)δ 3.63 (d, J=10.1 Hz, 1H, CHH_(a)), 3.52 (d, J=10.1 Hz, 1H, CHH_(b)),1.35 (s, 3H, Me); IR (KBr) 3434 (OH), 3300-2500 (COOH), 1730 (C═O),1449, 1421, 1380, 1292, 1193, 1085 cm⁻¹; [α]_(D) ²⁶+10.5° (c=2.6, MeOH);Anal. Calcd. for C₄H₇BrO₃: C, 26.25; H, 3.86. Found: C, 26.28; H, 3.75.

Synthesis of(2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide

Thionyl chloride (46.02 g, 0.39 mol) was added dropwise to a cooledsolution (less than 4° C.) of (R)-3-bromo-2-hydroxy-2-methylpropanoicacid (51.13 g, 0.28 mol) in 300 mL of THF under an argon atmosphere. Theresulting mixture was stirred for 3 h under the same condition. To thiswas added Et₃N (39.14 g, 0.39 mol) and stirred for 20 min under the samecondition. After 20 min, 5-amino-2-cyanobenzotrifluoride (40.0 g, 0.21mol), 400 mL of THF were added and then the mixture was allowed to stirovernight at room temperature. The solvent was removed under reducedpressure to give a solid which was treated with 300 mL of H₂O, extractedwith EtOAc (2×400 mL). The combined organic extracts were washed withsaturated NaHCO₃ solution (2×300 mL) and brine (300 mL). The organiclayer was dried over MgSO₄ and concentrated under reduced pressure togive a solid which was purified from column chromatography usingCH₂Cl₂/EtOAc (80:20) to give a solid. This solid was recrystallized fromCH₂Cl₂/hexane to give 55.8 g (73.9%) of(2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamideas a light-yellow solid.

¹H NMR (CDCl₃/TMS) δ 1.66 (s, 3H, CH₃), 3.11 (s, 1H, OH), 3.63 (d,J=10.8 Hz, 1H, CH₂), 4.05 (d, J=10.8 Hz, 1H, CH₂), 7.85 (d, J=8.4 Hz,1H, ArH), 7.99 (dd, J=2.1, 8.4 Hz, 1H, ArH), 8.12 (d, J=2.1 Hz, 1H,ArH), 9.04 (bs, 1H, NH). Calculated Mass: 349.99, [M-H]⁻ 349.0. M.p.:124-126° C.

Synthesis of(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide

A mixture of bromoamide((2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide,50 g, 0.14 mol), anhydrous K₂CO₃ (59.04 g, 0.43 mol), 4-cyanophenol(25.44 g, 0.21 mol) in 500 mL of 2-propanol was heated to reflux for 3 hand then concentrated under reduced pressure to give a solid. Theresulting residue was treated with 500 mL of H₂O and then extracted withEtOAc (2×300 mL). The combined EtOAc extracts were washed with 10% NaOH(4×200 mL) and brine. The organic layer was dried over MgSO₄ and thenconcentrated under reduced pressure to give an oil which was treatedwith 300 mL of ethanol and an activated carbon. The reaction mixture washeated to reflux for 1 h and then the hot mixture was filtered throughCelite. The filtrate was concentrated under reduced pressure to give anoil. This oil was purified by column chromatography using CH₂Cl₂/EtOAc(80:20) to give an oil which was crystallized from CH₂Cl₂/hexane to give33.2 g (59.9%) of(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideas a colorless solid (a cotton type).

¹H NMR (CDCl₃/TMS) δ 1.63 (s, 3H, CH₃), 3.35 (s, 1H₂OH), 4.07 (d, J=9.04Hz, 1H, CH), 4.51 (d, J=9.04 Hz, 1H, CH), 6.97-6.99 (m, 2H, ArH),7.57-7.60 (m, 2H, ArH), 7.81 (d, J=8.55 Hz, 1H, ArH), 7.97 (dd, J=1.95,8.55 Hz, 1H, ArH), 8.12 (d, J=1.95 Hz, 1H, ArH), 9.13 (bs, 1H, NH).Calculated Mass: 389.10, [M-H]⁻ 388.1. Mp: 92-94° C.

Example 15 Androgenic & Anabolic Activity in Intact and ORX Rats ofCompound of Formula S-XXV Materials and Methods

Male Sprague-Dawley rats weighing approximately 200 g were purchasedfrom Harlan Bioproducts for Science (Indianapolis, Ind.). The animalswere maintained on a 12-h light/dark cycle with food (7012C LM-485Mouse/Rat Sterilizable Diet, Harlan Teklad, Madison, Wis.) and wateravailable ad libitum. The animal protocol was reviewed and approved bythe Institutional Animal Care and Use Committee of the University ofTennessee. Anabolic and androgenic activity of compound of formula S-XXVin intact animals was evaluated, and the dose response in acutelyorchidectomized (ORX) animals was evaluated as well. Regenerativeeffects of Compound III in chronically (9 days) ORX rats were alsoassessed.

The compound was weighed and dissolved in 10% DMSO (Fisher) diluted withPEG 300 (Acros Organics, N.J.) for preparation of the appropriate dosageconcentrations. The animals were housed in groups of 2 to 3 animals percage. Intact and ORX animals were randomly assigned to one of sevengroups consisting of 4 to 5 animals per group. Control groups (intactand ORX) were administered vehicle daily. Compound of formula S-XXV wasadministered via oral gavage at doses of 0.01, 0.03, 0.1, 0.3, 0.75, and1 mg/day to both intact and ORX groups.

Castrated animals (on day one of the study) were randomly assigned todose groups (4-5 animals/group) of 0.01, 0.03, 0.1, 0.3, 0.75, and 1mg/day, for dose-response evaluation. Dosing began nine days post ORXand was administered daily via oral gavage for fourteen days. Theanimals were sacrificed under anesthesia (ketamine/xyalzine, 87:13mg/kg) after a 14-day dosing regimen, and body weights were recorded. Inaddition, ventral prostate, seminal vesicles, and levator ani musclewere removed, individually weighed, normalized to body weight, andexpressed as a percentage of intact control. Student's T-test was usedto compare individual dose groups to the intact control group.Significance was defined a priori as a P-value<0.05. As a measure ofandrogenic activity, ventral prostate and seminal vesicle weights wereevaluated, whereas levator ani muscle weight was evaluated as a measureof anabolic activity. Blood was collected from the abdominal aorta,centrifuged, and sera were frozen at −80° C. prior to determination ofserum hormone levels. Serum lutenizing hormone (LH) and folliclestimulating hormone (FSH) concentrations were determined.

Results

Prostate weights following compound of formula S-XXV treatment were111%±21%, 88%±15%, 77%±17%, 71%±16%, 71%±10%, and 87%±13% of intactcontrols following doses of 0.01, 0.03, 0.1, 0.3, 0.75, and 1 mg/day,respectively. Similarly, seminal vesicle weights decreased to 94%±9%,77%±11%, 80%±9%, 73%±12%, 77%±10%, and 88%±14% of intact controlsfollowing doses of 0.01, 0.03, 0.1, 0.3, 0.75, and 1 mg/day,respectively. Significant increases were seen in levator ani muscleweights of sham animals, however, in all dose groups, when compared tointact controls. The levator ani muscle weights were 120%±12%, 116%±7%,128%±7%, 134%±7%, 125%±9%, and 146%±17% of intact controls correspondingto 0.01, 0.03, 0.1, 0.3, 0.75, and 1.0 mg/day dose groups, respectively.

Compound of formula S-XXV partially maintained prostate weight followingorchidectomy. Prostate weight in vehicle treated ORX controls decreasedto 5%±1% of intact controls. At doses of 0.01, 0.03, 0.1, 0.3, 0.75, and1.0 mg/day, compound of formula S-XXV maintained prostate weights at8%±2%, 20%±5%, 51%±19%, 56%±9%, 80%±28%, and 74±12.5% of intactcontrols, respectively. In castrated controls, seminal vesicle weightdecreased to 13%±2% of intact controls. Compound of formula S-XXVpartially maintained seminal vesicle weights in ORX animals. Seminalvesicle weights from drug treated animals were 12%±4%, 17%±5%, 35%±10%,61%±15%, 70%±14%, and 80%±6% of intact controls, following doses of0.01, 0.03, 0.1, 0.3, 0.75, and 1.0 mg/day, respectively. In ORXcontrols the levator ani muscle weight decreased to 55%±7% of intactcontrols. We observed an anabolic effect in the levator ani muscle ofcompound of formula S-XXV treated animals. Compound of formula S-XXVfully maintained levator ani muscle weights at doses >0.1 mg/day.Doses >0.1 mg/day resulted in significant increases in levator aniweight compared to that observed in intact controls. Levator ani muscleweights as a percentage of intact controls were 59%±6%, 85%±9%,112%±10%, 122%±16%, 127±12%, and 129.66±2% for the 0.01, 0.03, 0.1, 0.3,0.75, and 1.0 mg/day dose groups, respectively. E_(max) and ED₅₀ valueswere determined in each tissue by nonlinear regression analysis inWinNonlin® and presented in FIG. 13. E_(max) values were 83%±25%,85%±11%, and 131%±2% for prostate, seminal vesicles, and levator ani,respectively. The ED₅₀ in prostate, seminal vesicles, and levator aniwas 0.09±0.07, 0.17±0.05, and 0.02±0.01 mg/day, respectively.

It will be appreciated by a person skilled in the art that the presentinvention is not limited by what has been particularly shown anddescribed hereinabove. Rather, the scope of the invention is defined bythe claims that follow:

What is claimed is:
 1. A method of enhancing production of lean meats ina feedlot animal, a beef cattle, or a finishing livestock comprisingadministering a compound represented by the structure of formula IIIA:

wherein Z is NO₂, CN, Cl, F, Br, I, H, COR, COOH, or CONHR; Y is CF₃,alkoxy, alkyl, hydroxyalkyl, alkylaldehyde, formyl, H, F, Br, Cl, I, CN,or Sn(R)₃; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl or OH; R₂ is H, F, Cl, Br,I, CH₃, CF₃, OH, CN, NO₂, NHCOCH₃, NHCOCF₃, NHCOR, alkyl, arylalkyl, OR,NH₂, NHR, N(R)₂, or SR; R₃ is H, F, Cl, Br, I, CN, NO₂, COR, COOH,CONHR, CF₃, or Sn(R)₃; Q is H, alkyl, halogen, CF₃, CN, C(R)₃, Sn(R)₃,N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OH, OR, COR, OCOR, OSO₂R, SO₂R, or SR;n is an integer of 1-4; and m is an integer of 1-3; or its isomer,pharmaceutically acceptable salt, pharmaceutical product, or anycombination thereof.
 2. The method of claim 1, wherein said feedlotanimal or finishing livestock is a pig or chicken.
 3. The method ofclaim 1, wherein said method comprises feeding said animal a daily feedwherein said feed comprises said compound of formula IIIA.
 4. The methodof claim 1, wherein said method comprises feeding said animal a dailyfeed wherein said feed comprises a compound of formula IIIA and abeta-adrenergic agonist.
 5. The method of claim 4, wherein saidbeta-adrenergic agonist is ractopamine hydrochloride.
 6. The method ofclaim 1, wherein said administering comprises administering saidcompound via an implant.
 7. The method of claim 6, wherein said implantcomprises a controlled release implant.
 8. The method of claim 6,wherein said feedlot animal or finishing livestock is a pig or chicken.9. The method of claim 1, wherein said administering comprises topicaladministration.
 10. The method of claim 9, wherein said topicaladministration comprises administering a topical spray, a topical creamor a topical ointment, or any combination thereof.
 11. The method ofclaim 9, wherein said feedlot animal or finishing livestock is a pig orchicken.
 12. The method of claim 1, wherein said compound is a compoundof formula (I):

wherein Q₂ is alkyl, F, Cl, Br, I, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂,NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, or SR; andR is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH.
 13. The method ofclaim 1, wherein said compound is a compound of formula S-II, S-XXIII,S-XXIV, or S-XXV: